Quinolizinone type compounds

ABSTRACT

Antibacterial compounds having the formula ##STR1## and the pharmaceutically acceptable salts, esters and amides thereof, selected preferred examples of which include those compounds wherein 
     A is═CR 6  --; 
     R 1  is cycloalkyl of from three to eight carbon atoms or substituted phenyl; 
     R 2  is selected from the group consisting of ##STR2## R 3  is halogen; R 4  is hydrogen, loweralkyl, a pharmaceutically acceptable cation, or a prodrug ester group; 
     R 5  is hydrogen, loweralkyl, halo(loweralkyl), or --NR 13  R 14  ; and 
     R 6  is halogen, loweralkyl, halo(loweralkyl), hydroxy-substituted loweralkyl, loweralkoxy(loweralkyl), loweralkoxy, or amino(loweralkyl), 
     as well as pharmaceutical compositions containing such compounds and the use of the same in the treatment of bacterial infections.

This application is a divisional of prior application U.S. Ser. No.08/469,159, filed on Jun. 6, 1995, which is a continuation-in-part ofU.S. Ser. No. 08/316,319, filed Sep. 30, 1994, which is acontinuation-in-part of U.S. Ser. No. 08/137,236, filed Oct. 14, 1993,now abandoned which is a continuation-in-part of U.S. Ser. No.07/940,870, filed Oct. 27, 1992, now abandoned, which is acontinution-in-part of U.S. Ser. No. 07/517,780, filed May 2, 1990, nowabandoned.

TECHNICAL FIELD

The present invention relates to compounds having antimicrobialactivity, pharmaceutical compositions containing such compounds, methodsof treatment utilizing such compounds, and processes for their chemicalsynthesis. More particularly, this invention relates to novel4-oxo-4H-quinolizine-3-carboxylic acid compounds which are highlyeffective in the treatment of microbial and especially bacterialinfections, as well as compositions containing the same and thetherapeutic use of such compounds.

BACKGROUND OF THE INVENTION

There is a continuing need for new antibacterial agents. Although manycompounds are known which are useful in the treatment of Gram-positiveand Gram-negative bacterial infections as well as other microbialinfections, the widespread use of such compounds continues to give riseto resistant strains of microorganisms, i.e., strains of microorganismsagainst which a particular antibiotic or group of antibiotics, which waspreviously effective, is no longer useful. Also, known antibiotics maybe effective against only certain strains of microorganisms or havelimited activity against either Gram-positive or Gram-negative, aerobicor anaerobic organisms.

The therapeutic use of certain quinolizinone derivatives has beendescribed previously. For example, Y. Kitaura et al., in U.S. Pat. No.4,650,804, issued Mar. 17, 1987, have disclosed quinolizinone compoundshaving a tetrazolylcarbamoyl substituent which are useful for thetreatment of allergic and ulcer diseases. J. V. Heck and E. D. Thorsett,in European Patent Application No. 0308019, published Mar. 22, 1989;have disclosed the use of certain 4-oxo-4H-quinolizine-3-carboxylicacids and derivatives thereof for treating bacterial infections.However, there remains an ongoing need for novel compounds which haveimproved antimicrobial potency and/or different spectra of activity.

SUMMARY OF THE INVENTION

In one aspect of the present invention are disclosed compoundsrepresented by the following structural formula (I): ##STR3## as well asthe pharmaceutically acceptable salts, esters and amides thereof.

R¹ in formula (I) is selected from (a) loweralkyl, (b) loweralkenyl, (c)halo(lower-alkyl), (d) loweralkoxy, (e) cycloalkyl of from three toeight carbon atoms, (f) phenyl, (g) substituted phenyl, (h) halo, (i)cyano, (j) nitro, (k) bicycloalkyl, (l) loweralkynyl, (m)loweralkoxycarbonyl, (n) nitrogen-containing aromatic heterocycle, (o)halo-substituted nitrogen-containing aromatic heterocycle, (p) a 4-, 5-or 6-membered cyclic ether, and (q) --NR⁷ R⁸. The radicals R⁷ and R⁸ areindependently selected from hydrogen, loweralkyl and alkanoyl of fromone to eight carbon atoms or, taken together with the nitrogen atom towhich they are attached, R⁷ and R⁸ may form a 5-, 6- or 7-memberedheterocycle, preferably in which the remainder of the ring atoms arecarbon atoms.

R² in formula (I) is selected from (a) halogen, (b) loweralkyl, (c)loweralkenyl, (d) cycloalkyl of from three to eight carbons, (e)cycloalkenyl of from four to eight carbons, (f) loweralkoxy, (g)aryloxy, (h) aryl(loweralkyl)oxy, (i) aryl(loweralkyl), (j)cycloalkyl(loweralkyl), (k) amino, (l) (loweralkyl)amino, (m)aryl(loweralkyl)-amino, (n) hydroxy-substituted (loweralkyl)amino, (o)phenyl, (p) substituted phenyl, (q) bicyclic nitrogen-containingheterocycle, (r) nitrogen-containing aromatic heterocycle, (s)nitrogen-containing heterocycle having the formula ##STR4## (t)non-nitrogen-containing heterocycle having the formula ##STR5## Insubformula (Ia) above, x is zero, one, two or three, and R⁹ is either(i) --(CH₂)_(m) -- where m is one, two or three, or (ii) --(CH₂)_(n) R¹³(CH₂)_(p) -- where R¹³ is selected from --S--, --O-- and --NH--, R¹⁰ isCH₂, or when R⁹ is selected from option (i) may be O, S or N, n is oneor two, and p is one or two. When present, the radical(s) Y is/areindependently selected at each occurrence from the following:

(i) loweralkyl,

(ii) hydroxy,

(iii) halogen,

(iv) halo(loweralkyl),

(v) hydroxy-substituted loweralkyl,

(vi) loweralkenylamino,

(vii) loweralkylamino,

(viii) loweralkoxy,

(ix) (loweralkoxy)loweralkylamino,

(x) loweralkoxy(loweralkyl),

(xi) loweralkoxy(loweralkoxy)(loweralkyl),

(xii) hydroxy-substituted loweralkyl,

(xiii) imino,

(xiv) alkoxycarbonyl,

(xv) carbamoyl,

(xvi) aryl(loweralkyl),

(xvii) aminoxy

(xviii) amino(loweralkyl),

(xix) halo(loweralkyl)amino,

(xx) halo(loweralkyl)amino(loweralkyl),

(xxi) thioloweralkoxy(loweralkyl),

(xxii) aminothioloweralkoxy,

(xxiii) cycloalkyl of from three to six carbon atoms,

(xxiv) cycloalkyl(loweralkyl),

(xxv) cycloalkylamino,

(xxvi) phenyl,

(xxvii) substituted phenyl,

(xxviii) substituted phenyl(loweralkyl)

(xxix) nitrogen-containing aromatic heterocycle,

(xxx) --NR¹¹ R¹² where R¹¹ and R¹² are independently selected fromhydrogen and loweralkyl or, when one of R¹¹ and R¹² is hydrogen, theother is alkanoyl of from one to eight carbon atoms, an alpha-aminoacid, or a polypeptide residue of from two to five amino acids, and

(xxxi) --C(R²¹)(R²²)NH₂ where R²¹ and R²² are independently selectedfrom among hydrogen, loweralkyl, hydroxy-substituted loweralkyl,amino(loweralkyl), loweralkoxy(loweralkyl), thioloweralkoxy(loweralkyl),cycloalkyl of from three to six carbon atoms, and loweralkyl substitutedwith nitrogen-containing aromatic heterocycle (or, taken together withthe carbon atom to which they are attached, R²¹ and R²² form a ringstructure selected from cycloalkyl of from three to six carbon atoms andnitrogen-containing heterocycle).

In subformula (Ib) above, x is zero, one, two or three, and R³¹ is--(CH₂)_(q) R³² -- where R³² is selected from --S-- and --O--, q is one,two or three, and the radical(s) Y is/are as defined above.

R³ in formula (I) is selected from among hydrogen, halogen andloweralkoxy, while R⁴ is selected from hydrogen, loweralkyl, apharmaceutically acceptable cation, and a prodrug ester group.

R⁵ in formula (I) is selected from (a) hydrogen, (b) halogen, (c)hydroxy, (d) loweralkyl, (e) halo(loweralkyl), (f) loweralkoxy, and (g)--NR¹³ R¹⁴ where R¹³ and R¹⁴ are independently selected from amonghydrogen, loweralkyl, hydroxy-substituted loweralkyl,loweralkoxy(loweralkyl), and alkanoyl of from one to eight carbon atoms.

A in formula (I) is ═N-- or ═CR⁶ --, where R⁶ is selected from (a)hydrogen, (b) halogen, (c) loweralkyl, (d) halo(loweralkyl), (e)hydroxy-substituted loweralkyl, (f) loweralkoxy(loweralkyl), (h)loweralkoxy, and (i) amino(loweralkyl).

Alternatively, taken together with the atoms to which they are attached,R¹ and R⁶ may form a 6-membered saturated ring optionally containing anoxygen or a sulfur atom and optionally substituted with loweralkyl, soas to produce a tricyclic compound.

The compounds of the present invention are subject to the proviso that,if R⁵ in formula (I) is hydrogen, A is ═CR⁶ --, and R⁶ is hydrogen, thenR¹ may not be unsubstituted phenyl.

The above compounds of the invention are found to have a surprisingdegree of antimicrobial activity against a wide spectrum ofGram-positive and Gram-negative bacteria as well as enterobacteria.Susceptible organisms whose growth can be inhibited generally includeboth aerobic and anaerobic pathogens of the genera Staphylococcus,Lactobacillus, Micrococcus, Enterococcus, Streptococcus, Sarcina,Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinobacter,Proteus, Providencia, Citrobacter, Nisseria, Baccillus, Bacteroides,Camphylobacter, Peptococcus, Clostridium, Salmonella, Shigella,Legionella, Serratia, Haemophilus, Brucella and the like. It istherefore expected that the compounds of the present invention will beuseful in the treatment and prevention of susceptible bacterialinfections in both humans and lower animals. In addition, the compounds,by reason of their in vitro activity, may be used in scrub solutions forsurface inhibition of bacterial growth.

Accordingly, in a further aspect of the present invention are disclosedpharmaceutical compositions which are useful in the treatment andprophylaxis of bacterial and/or fungal infection in humans and animals,comprising a compound of the invention in combination with apharmaceutically acceptable carrier.

In yet another aspect of the present invention is disclosed a method oftreating and/or preventing microbial infections in human or animalpatients in need of such treatment, comprising the administration tosuch patients of a therapeutically effective amount of a compound of theinvention in amounts and for such a period of time as are sufficient toproduce the desired result.

In still another aspect of the present invention are disclosed syntheticschemes and processes which are useful in the preparation of thecompounds of the invention, as well as synthetic (chemical)intermediates which can be utilized therein.

DETAILED DESCRIPTION OF THE INVENTION

Included among the compounds of the present invention are those in whichA is ═CR⁶ -- and R⁶ is selected from among halogen, loweralkyl,halo(loweralkyl), hydroxy-substituted loweralkyl,loweralkoxy(loweralkyl), loweralkoxy, or amino(loweralkyl). A sub-classof such compounds, particularly preferred and found to be surprisinglyeffective antibacterial agents, comprises those in which R⁶ is methyl.In each case, more preferred compounds are those in which R³ is halogen(especially fluoro); R⁵ is hydrogen, loweralkyl, halo-(loweralkyl), or--NR¹³ R¹⁴ (where R¹³ and R¹⁴ are as previously defined); R¹ iscycloalkyl of from three to eight carbon atoms or substituted phenyl;and/or R⁶ is halogen, loweralkyl, or loweralkoxy.

The radical R² in the above compounds is preferably bicyclicnitrogen-containing heterocycle or a nitrogen-containing heterocycle ofthe formula ##STR6## or, even more preferably, R² is selected from amongradicals of the formulae ##STR7## In these radicals R², x is preferablyone or two, and Y is preferably either --NR¹¹ R¹² or --C(R²¹)(R²²)NH₂,where R¹¹, R¹², R²¹ and R²² are as defined above.

Especially preferred among the compounds of the present invention arethose having the general formula ##STR8## as well as thepharmaceutically acceptable salts, esters and amides thereof, in whichR² is either bicyclic nitrogen-containing heterocycle or anitrogen-containing heterocycle having the formula ##STR9## Of these,particularly preferred compounds are those in which R² is selected fromamong radicals having the formulae ##STR10## and especially those inwhich x is one or two and Y is --NR¹¹ R¹² or --C(R²¹)(R²²)NH₂.

Also included among the compounds of the present invention are thosewhich have the general formula ##STR11## as well as the pharmaceuticallyacceptable salts, esters and amides thereof, in which Z is --CH₂ --,--O-- or --S--; R¹⁶ is loweralkyl; and R², R³, R⁴ and R⁵ are as definedabove. Preferred among such compounds are those in which Z is --O-- andR² is a nitrogen-containing heterocycle of the formula ##STR12##

Particular compounds which are representative of the compounds of thepresent invention include the following:

3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6(H)-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

9-(2,4-difluorophenyl)-3-fluoro-2-(4-methylpiperazin-1-yl)-6(H)-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

3-fluoro-9-cyclopropyl-2-(4-methylpiperazin-1-yl)-6(H)-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

8-(3-aminopyrrolidin-1-yl)-1-ethyl-4H-quinolizin-4-one-3-carboxylicacid;

2-(3-aminopyrrolidin-1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-(3-aminopyrrolidin-1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

9-(2,4-difluorophenyl)-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-(3-aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-(3-(N-t-butoxycarbonyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-(3-aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid;

9-cyclopropyl-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

9-cyclopropyl-3-fluoro-2-(piperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

9-cyclopropyl-3-fluoro-2-(morpholin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

9-(2,4-difluorophenyl)-3-fluoro-2-(3-(N-(S)-norvalyl)aminopyrrolidin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-(3-(N-(S)-alanyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-(3-(N-(S)-alanyl-(S)-alanyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-((2S,4S)-4-acetamido-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid;

9-(2,4-difluorophenyl)-3-fluoro-2-(3-hydroxypyrrolin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-((2S,4S)-4-amino-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid;

8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(aminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(2S,4S-4-amino-2-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-aminoazetidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3(S)-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-methyl-1-piperazinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-piperazinyl-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-8-(2-((N-methyl)aminomethyl)-4-morpholinyl)-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(1,2,3,4-tetrahydro-2-isoquinolinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(5-amino-1,2,3,4-tetrahydro-2-isoquinolinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(1-pyrrolyl)-1-piperidinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(cis-3.5-dimethyl-1-piperazinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(2,7-diaza-7-bicyclo[3.3.0]oct-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-(1-pyrrolyl)-1-pyrrolidinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-8-(3-hydroxy-1-pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-9-chloro-7-fluoro-8-(3-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylicacid.

1cyclopropyl-8-(2,7-diaza-7-bicyclo[3.3.0]oct-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-(1-pyrrolyl)-1-pyrrolidinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-8-(3-hydroxy-1-pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-9-chloro-7-fluoro-8-(3-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-8-(3(R)-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid;

(3S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid;

3(R)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid;

9-fluoro-10-(1-morpholinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid;

(3S)-10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid;

3(S)-10-(3-aminomethyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid;

3(S)-10-((2S,4S)-4-amino-2-methyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid;

3(S)-9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid;

9-fluoro-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid;

8-(2,4-dimethyl-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(methylamino)-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(methylamino)-1-morpholinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(S)-(methylamino)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(S)-(1-(methylamino)methyl)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(S)-(1-(ethylamino)methyl)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(octahydropyrrolo[3,4-c]pyrrol-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(octahydropyrrolo[3,4-c]pyridin-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(cis-4-amino-3-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(trans-4-amino-3-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-methyl-4-spirocyclopropylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(2S,4S-4-amino-2-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-(fluoro)methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-dimethylaminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R)-8-(3-dimethylaminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3S,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-((R,S)-3-fluoropyrrloidine)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(4-(1-piperidyl)-1-piperidyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(4-(1-piperidyl)-1-piperidyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(4-(2-pyridyl)-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-((2-amino)thioethoxy)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-amino-3-methylpropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4H-quinolizine-3-carboxylicacid;

8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-amino-2-hydroxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4H-quinolizine-3-carboxylicacid;

(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(1-aminobutyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3-aminopyrrolidinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3-aminomethylpyrrolidinyl)-4H-quinolizine-3-carboxylicacid;

3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-norvalylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylicacid;

3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylicacid;

3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanyl-(S)-alanylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-6-methyl-4-oxo-8-(3-aminopyrrolidinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-4H-8-(1-imidazolyl)-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-amino-1-pyrrolidinyl)-1-ethyl-7-fluoro-4H-4-oxo-9-methyl-quinolizine-3-carboxylicacid;

8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-9-ethyl-7-fluoro-4H-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(1,2,3-triazol-1-yl)-1-pyrrolidinyl)quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(cis-3-amino-4-methyl-1-pyrrolidinyl)quinolizine-3-carboxylicacid;

8-(2-aminoethyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(ethylaminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-4H-9-methyl-8-(2-methyl-2,8-diaza-8-bicyclo[4.3.0]nonyl)-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-4H-8-((1S,4S)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl)-9-methyl-4-oxoquinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(2-pyridinyl)-1-pyrrolidinyl)-quinolizine-3-carboxylicacid;

8-((1R*,2S*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-((1R*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-((1a,5a,6a)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl))-1-cyclopropyl-9-methacid;

8-(trans-3-amino-4-fluoro-1-pyrrolidinyl))-1-cyclopropyl-9-methyl-7-fluoro-4H-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-4H-8-(1-homopiperazinyl))-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

7,9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo-1-phenyl-quinolizine-3-carboxylicacid;

8-(spiro-1,3-dioxacyclopentane[2.3]-1-piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-amino-4-methoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(4-amino-4-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(4-(2-hydroxyethyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(4-(methoxymethyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-amino-3-methylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-pyrrolylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-amino-3-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-amino-4-(1',3'-dioxolanyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-amino-4-hydroxy-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(4-(1-(N-ethylamino)methyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-8-(3-hydroxy-4-methylaminopyrrolidinyl)-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-aminomethylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(2-aminomethyl-4-morpholinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(1-(methylamino)methypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(methyl(methylenedioxy)methyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(S)-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(S)-(N-ethyl-N-methylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(4-(2'-(N-methylamino)methyl-1',3'-dioxolanyl)piperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan-1-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(3-fluoromethylpiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine;

1-cyclopropyl-8-(4-(N,N-dimethyl)aminopiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(6-amino-3-azabicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-((2-aza-4-(dimethylaminomethyl)bicyclo[4.3.0]non-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizinecarboxylic acid;

1-cyclopropyl-8-(3-aza-6-(L-alanylamino)-6-methylbicyclo[3.3.0]octane)-7-fluoro-9-methyl-4-oxo-4H-quinolizinecarboxylic acid;

(3R,1R)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(S)-(acetylamino)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-carbamoylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-hydroxypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-hydroxymethylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(R)-hydroxypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

(3R)-9-fluoro-3-methyl-10-(piperazin-1-yl)-2H, 3H, 6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;

1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-aminomethyl-3-fluoro-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(S)-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(R)-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(1-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid Diastereomer A;

8-(1-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid Diastereomer B;

8-(3-(1-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(S*)-(1-(S*)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(R)-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(S)-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(octahydropyrrolo[3,2-b]pyridin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(8-amino-6-azaspiro[3.4]oct-6-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(2-aminomethyl-4-hydroxypyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(R)-(aminomethyl)morpholin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-qinolizine-3-carboxylicacid;

8-(3-(R)-(L-alanylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(5-aminooctahydroindol-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(2-piperidyl)piperidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(5-amino-decahydroisoquinolin-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3,7-diazabicyclo[3.3.0]oct-3-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-carboxypyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(2,2,2-trifluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-((2-fluoroethyl)aminomethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3a-amino-octahydroisoindol-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(6-amino-2-aza-spiro[3.3]non-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid (Isomer (I));

8-(3-amino-3-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(S)-hydroxymethylazetidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-aminomethyl-3-trifluoromethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(octahydropyrrolo[3.4-c]pyrid-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(cyclopropylamino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(6-amino-2-aza-spiro[3.3]non-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid (Isomer (II));

8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid Isomer A;

8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid Isomer B;

8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(S)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(2-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(2-(S)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(2-(S)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(R)-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(S)-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(1-amino-1-cyclopropyl-methyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(R)-(pyrrolidin-2-(S)-yl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(aminomethyl)azetidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; and

8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

as well as the pharmaceutically acceptable salts, esters and amidesthereof.

Preferred among the above representative compounds of the invention arethe following:

8-(3-(aminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3(S)-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(1-aminobutyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;

8-(3-(S)-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan-1-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(6-amino-3-azabicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-((1R*,2S*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-((1R*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3S,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

(8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; and

8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4acid;

as well as the pharmaceutically acceptable salts, esters and amidesthereof.

Especially preferred among the representative compounds of the presentinvention are the following:

8-(3(S)-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

(3R,1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;

(8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; and

8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;

as well as the pharmaceutically acceptable salts: esters and amidesthereof.

It will be observed above and elsewhere in the disclosure that numerousasymmetric centers may exist in the compounds of the present inventionwhich will be found in the R or S configurations. Except where otherwisenoted, the present invention contemplates the various stereoisomers andmixtures thereof.

A number of defined terms are used herein to designate particularelements of the present invention. When so used, the following meaningsare intended:

The term "alkanoyl of from one to eight carbons" refers to a radical ofthe formula --C(O)R¹⁵ where R¹⁵ is hydrogen or an alkyl radical of fromone to eight carbon atoms including, but not limited to, acetyl andpivaloyl.

The term "alkyl" refers to saturated, straight- or branched-chainhydrocarbon radicals containing between one and ten carbon atomsincluding, but not limited to, methyl, ethyl, propyl, isopropyl,n-butyl, tert-butyl and neopentyl.

The terms "alpha-amino acid" and "polypeptide residue" refer,respectively, to a single amino acid and two to five amino acids eachjoined by amide (peptide) bonds. The amino acids may be any of thenaturally-occurring amino acids such as valine, phenylalanine andglycine or synthetic alpha-amino acids such as cyclohexylalanine, andfurther may be in either the L or D configuration or a mixture of thetwo isomers. Preferably, amino acid substituents are optically activeand have the L configuration.

The term "amino(loweralkyl)" refers to a loweralkyl radical havingappended thereto at least one amino substituent which in turn isoptionally substituted with one or two loweralkyl radicals or analpha-amino acid or polypeptide residue. Examples of amino(loweralkyl)groups include aminoethyl, aminomethyl and N,N-dimethylaminoethyl.

The term "aminooxy" refers to an amino group, optionally substitutedonce or twice with loweralkyl or halo(loweralkyl), which is appended tothe rest of the molecule via an oxygen atom; (e.g. --O--NR'R" wherein R'and R" are hydrogen, loweralkyl or halo(loweralkyl).

The term "aminothioloweralkoxy" refers to a thioloweralkoxy radicalhaving appended thereto an amino group, as for example aminothiomethoxyand 2-aminothioethoxy.

The term "aromatic group" refers to a C6-to-C10 cyclic radical which isaromatic according to Huckel's rule. Examples of aromatic groups includecarbocyclic aromatic radicals such as phenyl and naphthyl as well asnitrogen-containing aromatic heterocyclic radicals, defined below.

The term "aryl(loweralkyl)" refers to a loweralkyl radical havingappended thereto an aromatic hydrocarbon group, as for example benzyland phenylethyl.

The term "aryl(loweralkyl)amino" refers to an amino radical havingappended thereto an aryl(loweralkyl) group. Examples ofaryl(loweralkyl)amino groups include benzylamino and phenylethylamino.

The term "aryl(loweralkyl)oxy" refers to an aryl(loweralkyl) radicalwhich is joined to the rest of the molecule via an ether linkage (i.e.,through an oxygen atom). Examples of aryl(loweralkyl)oxy radicalsinclude benzyloxy and phenylethyloxy.

The term "aryloxy" refers to an aromatic hydrocarbon radical which isjoined to the rest of the molecule via an ether linkage (i.e., throughan oxygen atom), as for example phenoxy.

The term "bicycloalkyl" refers to a radical comprising a bridged,saturated or unsaturated hydrocarbon ring system having between five andnine carbon atoms in which two non-adjacent carbon atoms of a first ringare linked by an alkylene bridge of between one and three additionalcarbon atoms, the bicycloalkyl radical being optionally substituted withbetween one and three additional radicals selected from amongaryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl),amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy,halogen, and amino, (loweralkyl)amino or alkanoylamino of from one toeight carbon atoms in which the amino group may be further substitutedwith alkanoyl of from one to eight carbons, an alpha-amino acid or apolypeptide. Examples of bicycloalkyl radicals include, but are notlimited to, norbornyl, bicylo[2.2.1]hept-2-enyl andbicyclo[1.1.1]pentanyl.

The term "bicyclic nitrogen-containing heterocyclic group" refers to aradical comprising a bicyclic ring system in which the the rings are ofthe (a) fused, (b) bridged or (c) spiro form. Fused-ring bicyclicnitrogen-containing heterocyclic groups are those in which a firstnitrogen-containing heterocycle or aromatic heterocycle has fused to ita second saturated or unsaturated carbocyclic or heterocyclic ring ofbetween three and six atoms of which zero, one or two are heteratomsselected from S, O, and N. Both the first and the second ring may beoptionally substituted with between one and three additional radicals A²independently selected from among loweralkyl, halo(loweralkyl),hydroxy-substituted loweralkyl, hydroxy, halogen, amino(loweralkyl),alkanoylamino of from one to eight carbons, phenyl and --NR¹⁷ R¹⁸ whereR¹⁷ and R¹⁸ are independently hydrogen or loweralkyl or, when one ishydrogen, the other is an alpha-amino acid or a polypeptide residue.Examples of fused-ring bicyclic nitrogen-containing heterocyclicradicals are those having 5:3, 5:4, 5:5, 5:6 and 6:5 ring systems andinclude, but are not limited to, radicals of the formulae ##STR13##

Bridged-ring bicyclic nitrogen-containing heterocyclic groups are thoseselected the formulae ##STR14## and unsaturated derivatives thereof,where j and k are independently one, two or three, and A¹ is a carbonatom or a heteroatom selected from S, O and N, optionally substituted atany position with between one and three additional radicals A² is aspreviously defined.

Spiro-ring bicyclic nitrogen-containing heterocyclic groups are those inwhich a first nitrogen-containing heterocycle or aromatic heterocycle towhich is joined; by a single shared carbon atom, a second carbocyclic orheterocyclic ring of between three and six atoms of which zero, one ortwo are heteratoms selected from S, O, and N. Either the first or thesecond ring may be substituted with between one and three additionalradicals A², where A² is as previously defined. Examples of spiro-tingbicyclic nitrogen-containing heterocyclic radicals include, but are notlimited to, those having the formulae ##STR15##

The term "cyclic ether" refers to a 4- to 6-membered monocyclichydrocarbon radical containing an oxygen ring atom and joined to therest of the molecule via any of the carbon atoms including, but notlimited to, oxetane.

The term "cycloalkenyl of from four to eight carbons" refers to amono-unsaturated monocyclic hydrocarbon radical having from four toeight carbon atoms in the ring, including, but not limited to,cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, andoptionally substituted with between one and three additionals radicalsselected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl,halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl,hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino,(loweralkyl)amino or alkanoylamino of from one to eight carbon atoms inwhich the amino group may be further substituted with alkanoyl of fromone to eight carbons, an alpha-amino acid or a polypeptide.

The term "cycloalkyl of from three to eight carbons" refers to asaturated monocyclic hydrocarbon radical having from three to eightcarbon atoms in the ring and optionally substituted with between one andthree additional radicals selected from among aryl(loweralkyl),alkoxycarbonyl, loweralkyl, halo(loweralkyl),:amino(loweralkyl),hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, andamino, (lowerallcyl)amino or alkanoylamino of from one to eight carbonatoms in which the amino group may be further substituted with alkanoylof from one to eight carbons, an alpha-amino acid or a polypeptide.Examples of cycloalkyl radicals include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,1-fluoro-cyclopropyl, 2-fluorocyclopropyl and 2-aminocyclopropyl.

The term "cycloalkyl(amino)" refers to an amino group substituted withat least one cycloalkyl group, typically having from three to eightcarbons.

The term "cycloalkyl(loweralkyl)" refers to a loweralkyl radical havingappended thereto a cycloalkyl radical of from three to eight carbonatoms, which cycloalkyl radical may be optionally substituted asdescribed above.

The term "fused" as used herein refers to two cyclic groups having twoadjacent ring atoms in common.

The terms "halo" and "halogen" refer to a monovalent radical selectedfrom among chloro (Cl), bromo (Br), fluoro (F) and iodo (I).

The term "halo(loweralkyl)" refers to a loweralkyl radical havingappended thereto between one and three halogen atoms. Examples ofhalo(loweralkyl) radicals include fluoromethyl, trifluoromethyl,1-fluoroethyl, 2-fluoroethyl and 1,2-difluoroethyl.

The term "halo(loweralkyl)amino" refers to an amino group substitutedwith at least one halo(loweralkyl) group.

The term "halo(loweralkyl)amino(loweralkyl)" refers to anamino(loweralkyl) radical having appended thereto a halo(loweralkyl)group, as for example 2-fluoroethylaminomethyl.

The term "halo-substituted nitrogen-containing aromatic heterocycle"refers to a nitrogen-containing aromatic heterocycle radical havingappended thereto between one and three halogen atoms including, but notlimited to, 5-fluoro-2-pyrimidyl.

The term "hydroxy-substituted loweralkyl" refers to a loweralkyl radicalhaving appended thereto between one and three hydroxyl groups, as forexample hydroxymethyl and 2-hydroxyethyl.

The term "hydroxy-substituted (loweralkyl)amino" refers to a(loweralkyl)amino radical having appended thereto between one and threehydroxyl groups, as for example hydroxymethylamino and2-hydroxyethylamino.

The term "imino" refers to a divalent radical of the formula ═N--OH.

The term "loweralkenyl" refers to a straight- or branched-chainhydrocarbon radical containing between two and six carbon atoms andpossessing at least one carbon-carbon double bond. Examples ofloweralkenyl radicals include vinyl, allyl, 2- or 3-butenyl, 2-,3- or4-pentenyl, 2-,3-,4- or 5-hexenyl and isomeric forms thereof.

The term "loweralkoxy" refers to a loweralkyl radical which is appendedto the rest of the molecule via an ether linkage (i.e., through anoxygen atom), as for example methoxy, ethoxy, propoxy, tert-butoxy,pentyloxy, hexyloxy, isomeric forms thereof and the like.

The term "loweralkoxycarbonyl" refers to a radical of the formula--C(O)R²⁵ wherein R²⁵ is a loweralkoxy group, as for exampleethoxycarbonyl and methoxycarbonyl.

The term "loweralkoxy(loweralkoxy)(loweralkyl)" refers to aloweralkoxy(loweralkyl) radical having appended thereto a loweralkoxygroup, as for example methoxymethoxymethyl and ethoxymethoxymethyl.

The term "loweralkoxy(loweralkyl)" refers to a loweralkyl radical havingappended thereto a loweralkoxy group and optionally substituted with anadditional amino radical, as for example methoxyethyl, ethoxymethyl and1-amino-2-methoxyethyl.

The term "loweralkyl" refers to an alkyl radical containing one to sixcarbon atoms including, but not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl and neopentyl.

The term "(loweralkyl)amino" refers to an amino radical substituted withbetween one and three loweralkyl radicals including, but not limited to,methylamino, ethylamino, dimethylamino, propylamino andethylmethylamino.

The term "loweralkynyl" refers to a straight- or branched-chainhydrocarbon radical containing between two and six carbon atoms andpossessing at least one carbon-carbon triple bond. Examples ofloweralkynyl radicals include ethynyl, 2-hexyn-1-yl,3,3-dimethyl-1-butyn-1-yl and 3-methylbutyn-3-yl.

The term "nitrogen-containing aromatic heterocycle" refers to amonocyclic aromatic radical having from five to seven ring atoms ofwhich one ring atom is nitrogen; zero, one or two ring atoms areadditional heteroatoms independently selected from S, O and N; and theremaining ring atoms are carbon, the radical being joined to the rest ofthe molecule via any of the ring atoms. Examples of nitrogen-containingaromatic heterocycles include pyridine, pyrazine, pyrimidine, pyrrole,pyrazole, imidazole, thiazole, oxazole, isooxazole, thiadiazole,oxadiazole and substituted derivatives thereof.

The term "nitrogen-containing heterocycle" refers to a saturated orunsaturated monocyclic ring system radical having from four to sevenring atoms of which one is nitrogen; zero, one or two are additionalheteroatoms independently selected from S, O and N; and the remainderare carbon, the radical being joined to the rest of the molecule via anyof the ring atoms and being optionally substituted, either on a nitrogenor a carbon atom, by an additional radical selected from amongaryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl),amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy,halogen, amino, loweralkylamino, and amino, (loweralkyl)amino oralkanoylamino of from one to eight carbon atoms in which the amino groupmay be further substituted with alkanoyl of from one to eight carbons,an alpha-amino acid or a polypeptide. Examples of nitrogen-containingheterocycles include pyrrolidine, dihydropylrole, isooxazolidine,oxazolidine, tetrhydropyridine, piperidine, piperazine, morpholine,thiomorpholine, aziridine and azetidine.

The term "pharmaceutically acceptable cation" refers to apositively-charged inorganic or organic ion that is generally consideredsuitable for human consumption. Examples of pharmaceutically acceptablecations are hydrogen, alkali metal (lithium, sodium and potassium),magnesium, calcium, ferrous, ferric, ammonium, alkylammonium,dialkylammonium, trialkylammonium, tetraalkylammonium,diethanolammmonium, triethanolammonium, and guanidinium ions, andprotonated forms of lysine, procaine and choline. Cations may beinterchanged by methods known in the art, such as ion exchange. Wherecompounds of the present invention are prepared in the carboxylic acidform (that is, where R₄ is hydrogen) addition of a base form of thecation, (such as a hydroxide or a free amine) will yield the appropriatecationic form.

By "pharmaceutically acceptable salts, esters and amides", as of thecompounds of formula I, is meant those carboxylate salts, amino acidaddition salts, esters and amides which are, within the scope of soundmedical judgement, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms thereof.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M Berge et al. describe pharmaceutically acceptable salts indetail in J. Pharmaceutical Sciences, 66:1-19 (1977). Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, surfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include nitrate, bisulfate, borate,formate, butyrate, valerate, 3-phenylpropionate, camphorate, adipate,benzoate, oleate, palmitate, stearate, laurate, lactate, fumarate,ascotbate, aspartate, nicotinate, p-toluenesulfonate, camphorsulfonate,methanesulfonate, 2-hydroxyethanesulfonate, gluconate, glucoheptonate,lactobionate, glycerophosphate, pectinate, lauryl surfate and the likeor metal salts such as sodium, potassium, magnesium or calcium salts oramino salts such as ammonium, triethylamine salts and the like, all ofwhich may be prepared according to conventional methods.

Examples of pharmaceutically acceptable, non-toxic esters of the presentinvention include C1-to-C6 alkyl esters and C5-to-C7 cycloalkyl esters,although C1-to-C4 alkyl esters are preferred. Esters of the compounds offormula I may be prepared according to conventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of the presentinvention include amides derived from ammonia, primary C1-to-C6 alkylamines and secondary C1-to-C6 dialkyl amines. In the case of secondaryamines, the amine may also be in the form of a 5- or 6-memberedheterocycle containing one nitrogen atom. Amides derived from ammonia,C1-to-C3 alkyl primary amides and C1-to-C2 dialkyl secondary amides arepreferred. Amides of the compounds of formula I may be preparedaccording to conventional methods. It is intended that amides of thepresent invention include amino acid and peptide derivatives of thecompounds of formula I as well.

As used herein, the term "pharmaceutically acceptable carrier" means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of the materials that can serve as pharmaceutically acceptablecarriers are sugars, such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols such as glycerin, sorbitol, mannitoland polyethylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol and phosphate buffer solutions, as well as othernon-toxic compatible substances used in pharmaceutical formulations.Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfateand magnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents, andpreservatives can also be present in the composition, according to thejudgement of the formulator.

The term "prodrug", as of the compounds of formula I, refers toderivative compounds that are rapidly transformed in vivo to yield theparent compound of the formula I, as for example by hydrolysis in blood.T. Higuchi and V. Stella provide a thorough discussion of the prodrugconcept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S.Symposium Series, American Chemical Society (1975). Examples of estersuseful as prodrugs for compounds containing carboxyl groups can be foundon pages 14-21 of "Bioreversible Carriers in Drug Design: Theory andApplication", edited by E. B. Roche, Pergamon Press:New York (1987). Itis intended that these references, and any others cited throughout thisspecification, are incorporated herein by reference.

The term "prodrug ester group" refers to any of several ester-forminggroups that are hydrolyzed under physiological conditions. Examples ofprodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl,indanyl and methoxymethyl, as well as other such groups known in theart, including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group. Otherexamples of prodrug ester groups can be found in the book "Pro-drugs asNovel Delivery Systems", by Higuchi and Stella, cited above.

The term "protecting group" is well-known in the art and refers tosubstituents on functional groups of compounds undergoing chemicaltransformation which prevent undesired reactions and degradations duringa synthesis; see, for example, T. H. Greene, "Protective Groups inOrganic Synthesis", John Whey & Sons, New York (1981).

The term "substituted phenyl" refers to a benzene ring having betweenone and five non-hydrogen substituents, each independently selected fromamong halogen, hydroxy, loweralkoxy, loweralkyl, hydroxy-substitutedloweralkyl, amino, (loweralkyl)amino, amino(loweralkyl) andnitrogen-containing heterocycle. Examples of substituted phenyl radicalsinclude 2-fluorophenyl, 4-fluorophenyl and 2,4-difluorophenyl.

The term "thioloweralkoxy" refers to a radical of the formula --SR³⁵where R³⁵ is a loweralkyl group including, but not limited to,thiomethoxy and thioethoxy.

The term "thioloweralkoxy(loweralkyl)" refers to a loweralkyl radicalhaving appended thereto a thioloweralkoxy group including, but notlimited to, thiomethoxymethyl and thiomethoxyethyl.

According to the methods of treatment of the present invention, thecompounds of the invention may be administered alone or in combinationor in concurrent therapy with other agents. When utilizing the compoundsof the present invention for antimicrobial therapy, the specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; activity of the particular compoundused; the specific composition employed; the age, body weight, generalhealth, sex and diet of the patient; the time of administration, routeof administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidently with the specific compound employed; and like factors wellknown in the medical arts.

The total daily dose of the compounds of this invention administered toa host in single or in divided doses can be in amounts, as for examplefrom 0.1 to 200 mg/kg body weight or more usually from 0.25 to 100 mg/kgbody weight. Single dose compositions may contain such amounts orsubmultiples thereof as make up the daily dose.

According to the pharmaceutical compositions of the present invention,the compounds of the invention may be administered orally, parenterally,by inhalation spray, rectally, or topically in unit dosage formulationscontaining conventional nontoxic pharmaceutically acceptable carriers,adjuvants, diluents ancot vehicles as desired. The term "parenteral" asused herein includes subcutaneous injections, intravenous,intramuscular, intrastemal injection or infusion techniques.

Injectable preparations, as for example sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known anusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,as for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,U.S.P. and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil can be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid are used in the preparation of injectables.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of a drug from subcutaneous or intramuscular injection.The most common way to accomplish this is to inject a suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug becomes dependent on the rate of dissolutionof the drug which is, in turn, dependent on the physical state of thedrug, for example, the crystal size and the crystalline form. Anotherapproach to delaying absorption of a drug is to administer the drug as asolution or suspension in oil. Injectable depot forms can also be madeby forming microcapsule matrices of drugs and biodegradable polymerssuch as polylactide-polyglycolide. Depending on the ratio of drug topolymer and the composition of the polymer, the rate of drug release canbe controlled. Examples of other biodegradable polymers includepoly-orthoesters and polyanhydrides. Depot injectables can also be madeby entrapping the drug in liposomes or microemulsions which arecompatible with body tissues.

Suppositories for rectal or vaginal administration of the chug can beprepared by mixing the drug with a suitable nonirritating excipient suchas cocoa butter and polyethylene glycol which are solid at ordinarytemperature but will melt in the rectum or in the vagina and release thedrug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, prills and granules. In such solid dosage formsthe active compound may be admixed with at least one inert diluent suchas sucrose, lactose or starch. Such dosage forms may also comprise, asis normal practice, additional substances other than inert diluents,e.g., tableting lubricants and other tableting aids such as magnesiumstearate and microcrystalline cellulose. In the case of capsules,tablets and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings andother release-controlling coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs containing inert diluents commonly used in the an such as water.Such compositions may also comprise adjuvants, such as wetting agents;emulsifying and suspending agents; and sweetening, flavoring andperfuming agents.

If desired, the compounds of the present invention can be incorporatedinto slow release or targeted delivery systems such as polymer matrices,liposomes and microspheres. They may be sterilized, for example, byfiltration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which candissolve in sterile water, or some other sterile injectable mediumimmediately before use.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above.

Dosage forms for topical or transdermal administration of a compound ofthis invention further include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulations, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons or substitutes therefor.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispersing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

A further possibility for delivery and/or utilization of the compoundsof the present invention is by chemical conjugation of the compoundswith other antibacterials such as beta-lactams. Similar dual-actionconjugates (between beta-lactams and quinolones) are proposed in thepublished European patent application No. 597 303 of Dax et al.(published on May 18, 1994) and the published international patentapplication No. PCT/US92/08246 of White et al. (Publication No. WO93/07154, published on Apr. 15, 1993). In the manner suggested by thesereferences, a carbon-nitrogen bond or other covalent link may be formedbetween, for example, either an amino substituent at the C-8 position ora carboxylic acid group at the C-3 position of a compound of the presentinvention, and an alkyl or other group of a beta-lactam.

In general, the compounds of the present invention are synthesizedaccording to reaction Schemes I through XVIII presented below, in whichR¹ through R¹⁶, A, X, Y and Z correspond to the groups defined inconnection with formula (I), R is a loweralkyl group, X is a halogenatom, P is a protecting group and L is a suitable leaving group, as forexample a halogen atom.

Certain abbreviations are used repeatedly in the specification whichfollows. These include: BOC for t-butoxycarbonyl; (BOC)₂ for di-t-butyldicarbonate; CBZ for benzyloxycarbonyl; DMF for dimethyl formamide; DMSOfor dimethyl sulfoxide; HRMS for high resolution mass spectroscopy; LAHfor lithium aluminum hydride; LDA for lithium diethyl amide; RaNi forRaney Nickel; and THF for tetrahydrofuran.

For the preparation of the compounds of formula (I) which arealpha-amino acid or peptide derivatives of amine groups at R², thecondensation of the amino group with amino acids and peptides may beeffected in accordance with conventional condensation methods such asthe azide method, the mixed acid anhydride method, the DCC(dicyclohexylcarbodiimide) method, the active ester method(p-nitrophenyl ester method, N-hydroxysuccinic acid imide ester method,cyanomethyl ester method and the like), the Woodward reagent K method,the DCC-HOBT (1-hydroxy-benzotriazole) method and the like. Classicalmethods for amino acid condensation reactions are described in "PeptideSynthesis", Second Edition, M. Bodansky, Y. S. Klausnet and M. A.Ondetti (1976). It is contemplated that the amino acid coupling reactioncould be carried out before or after the amino-containing group isincorporated into the compound by displacement of the 7-fluorine atom ofthe appropriate intermediate.

As in conventional peptide synthesis, branched chain amino and carboxylgroups at alpha and omega positions in amino acids may be protected anddeprotected if necessary. The protecting groups for amino groups whichcan be used involve, for example, benzyloxycarbonyl (Z),o-chloro-benzyloxycarbonyl((2-Cl)Z), p-nitrobenzyloxycarbonyl (Z(NO2)),p-methoxybenzyloxycarbonyl (Z(OMe)), t-butoxycarbonyl (Boc),t-amyloxycarbonyl (Aoc), isobornealoxycarbonyl, adamantyloxycarbonyl(Adoc), 2-(4-biphenyl)-2-propyloxy carbonyl (Bpoc),9-fluorenyl-methoxycarbonyl (Fmoc), methylsulfonylethoxy carbonyl (Msc),trifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulfenyl (Nps),diphenylphosphinothioyl (Ppt) and dimethylphosphino-thioyl (Mpt).

The examples of protecting groups for carboxyl groups involve, forexample, benzyl ester (OBzl), cyclohexyl ester, 4-nitrobenzyl ester(OBzlNO2), t-butyl ester (OtBu), 4-pyridylmethyl ester (OPic) and thelike.

In the course of the synthesis of certain of the compounds of thepresent invention, specific amino acids having functional groups otherthan amino and carboxyl groups in the branched chain such as arginine,cysteine, serine and the like may be protected, if necessary, withsuitable protecting groups. It is preferable that, for example, theguanidino group (NG) in arginine be protected with nitro,p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl(Adoc), p-methoxybenzenesulfonyl, 4-methoxy-2,6-dimethylbenzenesulfonyl(Mts) or the like; that the thiol group in cysteine be protected withbenzyl, p-methoxybenzyl, triphenylmethyl, acetamidomethyl,ethylcarbamyl, 4-methylbenzyl (4-MeBzl), 2,4,6,-trimethylbenzyl (Tmb) orthe like; and that the hydroxy group in serine may be protected withbenzyl (Bzl), t-butyl, acetyl, tetrahydropyranyl (THP) or the like.##STR16##

In accordance with reaction Scheme I, illustrated above, an alpha-haloacetate derivative of formula 1, such as ethyl 2-fluoroacetate, iscondensed with a formate ester of formula 2 in the presence of asuitable base, as for example sodium ethoxide, in an inert solvent suchas diethyl ether to to give an enolate compound of formula 3. Compoundsof formula 3 are, in turn, converted to compounds of formula 5 bycondensation with an amidine derivative of formula 4, in which R¹ is anelectron withdrawing group such as phenyl, trifluoromethyl, cyano,perfluoroalkyl, vinyl, substituted vinyl, fluorine, nitro, acetylene,substituted acetylene, alkoxycarbonyl, or a nitrogen-containing aromaticheterocycle. Compounds of formula 5 are reacted with an alkoxymethylenemalonate derivative of formula 8 in the presence of a suitable strongbase, for example lithium diisopropylamide (LDA) or n-butyl lithium,preferably at a temperature below 0° C., and conveniently at -78° C. toafford the compounds of formula 9A.

The compounds of formula 9A are cyclized in the presence of a base, asfor example DBU or piperidine, or in the presence of an acid, such assulfuric acid, in a solvent such as toluene, THF, ethanol orchlorobenzene, or by heating the compound in a solvent, as for examplexylene, diglyme, triglyme, suffolane or Dowtherm A® (a eutectic mixtureof biphenyl and diphenyl ether) at a temperature greater than 120° C.,to give the compounds of formula 10C. The esters 10C are converted intothe esters 11A via transesterification with an alcohol suitable forselective hydrolysis, such as benzyl alcohol or2-(trimethylsilyl)ethanol (TMSE), in the presence of a catalyst, as forexample titanium tetraethoxide.

The 2-hydroxy compounds of formula 11A are convened to the correspondinghalo-derivatives of formula 12A by treatment with a halogenating agent,for example phosphorous oxychloride to afford the chloro derivative,optionally in an inert solvent at a temperature between about 20° C. and145° C., depending on the halogenating agent and the boiling point ofthe solvent if one is used, and conveniently at room temperature. Theleaving group L in the compounds of formula 12A is then displaced by anucleophile such as a nucleophilic amine, for example N-methylpiperazineor 2-methylpiperazine, to give the compounds of formula 13A. Thereaction may be conducted at a temperature from about 20° C. to about130° C. in a suitable organic solvent such as pyridine, methylenechloride, chloroform or 1-methyl-2-pyrrolidinone. It is desirable tocarry out the reaction in the presence of an acid-acceptor such astriethylamine, potassium carbonate and the like, at a molar ratio of 1.0to 2.0 moles of the acid acceptor per mole of compound of the formula 6.The amine can also be used as an acid acceptor in which case two or moreequivalents of this reagent are used.

The benzyl ester group of compounds of formula 13A is then removed byhydrogenolysis when R^(*) is benzyl, or with tetrabutylammonium fluoridewhen R^(*) is TMSE, to afford a compound of formula I.

In accordance with Scheme II above, the substituted acetonitrilecompounds of formula 4B, where R¹ is an alkyl, cycloalkyl,halo(loweralkyl) group or a (loweralkyl)amino group protected with aprotecting group such as benzyloxycarbonyl, or may be an electronwithdrawing group as described above for Scheme I, are reacted withdiethyl carbonate and sodium hydride in an inert organic solvent, suchas toluene, THF or the like, to give the substituted cyanoacetic acidester of formula 5B. The cyano group of the compounds of formula 5B isthen reacted with an inorganic acid, such as hydrochloric acid, in thepresence of one equivalent of anhydrous alcohol, such as ethanol,followed by reaction with ammonia to give the substituted amidine esterof formula 6B, which is then condensed with an enolate compound offormula 7B, prepared in a-manner similar to compounds of formula 3 inScheme I, in the presence of a suitable base, for example triethylamine,in a polar solvent such as methanol to give the substitutedhydroxypyrimidine ester compounds of formula 8B. The ester function ofthe compounds of formula 8B is converted into an aldehyde function byreduction, for example with a hindered aluminum hydride, such asdiisobutylaluminum hydride or LiAlH(O-t-butyl)₃, or withN,N-dimethyl-chloromethyleneiminium chloride in pyridine ordiaminoaluminum hydride to produce a compound of formula 9B. Thisreaction may be conducted at a temperature below -20° C., andconveniently at -78° C. in the presence of a aprotic solvent such ashexane, toluene, methylene chloride or THF.

The aldehyde compounds of formula 9B are reacted with a malonic aciddiester, such as diethyl malonate, dibenzyl malonate, t-butyl malonateor di-t-butyl malonate, in the presence of a suitable base such aspiperidine and a catalytic amount of an acid, such as acetic acid orsulfuric acid, in a polar solvent, such as ethanol, to afford thepyridopyrimidine compounds of formula 10B. The compounds of formula 10Bare reacted with a suitable halogenating agent such as phosphorylchloride at room temperature to afford the compounds of formula 11B. Thehalo group is displaced as discussed in reaction Scheme I to afford thecompounds of formula 12B, which are in turn convened into the compoundsof formula I as described in Scheme I for the conversion of compounds offormula 10 into compounds of formula I.

According to reaction Scheme III illustrated above, 2-picoline-N-oxideis converted to a mixture of compounds of formulae 22 and 23 bytreatment with a halogenating agent, for example phosphorus oxychloride,optionally in an inert solvent. The reaction may be run at a temperaturebetween about 25° C. and 125° C., depending on the halogenating agentselected. When the halogenating agent is phosphorus oxychloride thereaction temperature is preferably between 60° C. and 120° C. A compoundof formula 23 is, in turn, reacted with an alkoxymethylene malonatederivative of formula 8 in the presence of a suitably strong andhindered base, for example lithium diisopropylamide (LDA), preferably ata temperature below 0° C., and conveniently at -78° C. to afford thecompounds of formula 24. Compounds of formula 24 are cyclized by heatingthe compound in a solvent with a boiling point greater than 120° C., forexample xylene, diglyme, triglyme, sulfolane or Dowtherm A® (a eutecticmixture of biphenyl and diphenyl ether), to afford compounds of formula25. The leaving group in the 8-position of the quinolizinone compound offormula 25 is then displaced using 3-aminopyrrolidine with the primaryamino group protected, for example with t-butoxycarbonyl,. Theprotecting group is then removed to give the compounds of formula 26.

The esters of formula 26 are than converted to the carboxylic acids offormula lII as described in Scheme 1 for the conversion of compounds offormula 10 to compounds of formula I.

Alternately, compounds of formula 23 are converted to compounds offormula 27, wherein R¹ is alkyl, cycloalkyl or carbocyclicaryl(loweralkyl), by treatment with an alkyl, cycloalkyl or carbocyclicaryl(loweralkyl) halide in the presence of a suitable base such as LDA.Compounds of formula 23 are converted to compounds of formula 27,wherein R¹ is a phenyl group as defined herein or an alkylamino group byconversion to the corresponding halomethyl compound and treatment of thehalomethyl compound with an aryl metal compound such as phenyllithium asdescribed above, or with an alkylamine such as methylamine as shown inreaction Scheme VA. The compounds of formula 27 are converted to thecompounds of formula 29 by the sequence of reactions described above forthe conversion of compounds of formula 25. The leaving group in the8-position of the quinolizinone compound of formula 29 is thendisplaced, for example by a nucleophilic amine such asN-methylpiperazine or 2-methylpiperazine, to give the the compounds offormula 30. The reaction may be conducted at a temperature from about20° C. to about 130° C. in a suitable organic solvent such as pyridine,methylene chloride, chloroform or 1-methyl-2-pyrrolidinone. It isdesirable to carry out the reaction in the presence of an acid-acceptorsuch as triethylamine, potassium carbonate and the like, at a molarratio of 1.0 to 2.0 moles of the acid acceptor per mole of compound ofthe formula29. The amine can also be used as an acid acceptor in whichcase two or more equivalents of this reagent are used.

In the case where R² is a phenyl group as defined herein, compounds offormula 30 are formed by coupling the compound of formula 29 with anaryl metal compound, for example phenyllithium, to replace the 8-leavinggroup with an unsubstituted phenyl group. The coupling reaction iscarried in a reaction-inert solvent, i.e., a solvent which does notinterfere with the coupling reaction of the aryl metal compound with acompound of formula29. Suitable reaction-inert solvents include ethers,for example diethyl ether, dimethoxyethane and tetrahydrofuran (THF).Co-solvents may be used with ethers if desired. These co-solvents may bebenzene, toluene, tetramethylethyleneamine (TMEDA) andhexamethyl-phosphoramide (HMPA). The aryl metal compounds may beprepared by known methods. For example, they may be prepared by directlithium-halogen exchange of the corresponding aryl halide usingn-butyl-, sec-butyl- or t-butyl-lithium followed by transmetallation bya wide variety of salts by known methods such as described by E. Negishiin "Organometallics in Organic Sysnthesis", Vol. 1, page 104.

According to Scheme IV A illustrated above, a compound of formula 31 istreated with a malononic acid ester, for example diethyl malonate, inthe presence of a suitable base such as sodium hydride in a polarnonprotic solvent such as an ether, for example diethyl ether or THF, toafford a compound of formula 32. Compounds of formula 32 are, in turn,decarboxylated, for example by heating them in strong mineral acid suchas aqueous surfuric acid, to afford the compounds of formula 33. Thenitro-compound of formula 33 is reduced to the correspondingamino-compound of formula 34. The nitro group may be reduced bycatalytic hydrogenation using standard techniques or by any of a varietyof known reducing agents such as using a metal, for example zinc, tin oriron, in the presence of a mineral acid, usually hydrochloric acid. Theamino-compound of formula 34 is converted to the correspondingfluoro-compound of formula 35 by treatment with ethyl nitrite andtetrafluoroboric acid, followed by treatment with potassium fluoride.The compound of formula 35 is then converted into the correspondingN-oxide of formula 36 by oxidation, for example using peracetic acid.The reaction is carded out in the range from about 20° C. up to thereflux temperature of the solvent employed, preferably at about 50° C.The compound of formula 36 is nitrated to afford compounds of formula37. The nitration reaction can be carried out using a variety of knownnitrating agents, for example a mixture of nitric acid and surfuric acidor a mixture of sulfuric acid and potassium nitrate, or by usingnitronium salts such as nitronium trifluoromethanesulfonate. The nitrocompound of formula 37 is, in turn, converted to the corresponding halocompound of formula 38 by treatment with mineral acid at ambient orelevated temperature as desired. For example, the compound of formula 37is treated with aqueous hydrochloric acid at a temperature of about100°-120° C. to afford the compound of formula 38 wherein L is Cl. Thecompound of formula 38 is, in turn converted to the compound of formulaIV A1 by reduction, for example using a metal such as iron or zinc inthe presence of an acid such as acetic acid. The compound of formula IVA 1 is, in turn, converted to the compound of formula IV A2 by treatmentwith a suitable base, such as LDA, followed by treatment with ahalogenating agent, for example N-chloro or N-bromo succinimide.Alternately, the compounds of formula IV A1 are converted to compoundsof formula IV A3, wherein R¹ is alkyl, cycloalkyl or carbocyclicaryl(loweralkyl), by treatment with an alkyl, cycloalkyl or carbocyclicaryl(loweralkyl) halide in the presence of a suitable base such as LDA.The compounds of formula IV A3 are further treated with a a suitablebase, such as LDA, followed by treatment with a halogenating agent, forexample N-chloro or N-bromo succinimide to afford the compounds offormula IV A4. Compounds of formulae IV A1-IV A4 are key intermediatesused in the synthesis of quinolizinone compounds.

According to Schemes IV B and IV C illustrated above, the compounds offormulae IV A3 and IV A4 are converted to the quinolizinone compounds offormula IV B and IV C, respectively, by the following series ofreactions: (1) reaction with an alkoxymethylene malonate derivative offormula 8 in the presence of a suitably strong and hindered base, forexample lithium diisopropylamide (LDA), preferably at a temperaturebelow 0° C., and conveniently at -78° C., to afford the compounds offormulae 39 and 42, respectively (2) cyclization as discussed inreaction Scheme III, to afford the compounds of formulae 40 and 43,respectively (3) displacement of the leaving group in the 8-position asdiscussed in reaction Scheme III to afford the compounds of formulae 41and 44, respectively and (4) hydrolysis or hydrogenolysis as discussedin reaction Scheme III of the carboxylic acid ester to the correspondingcarboxylic acids of formulae IV B and IV C, respectively.

According to Scheme V A illustrated above, compounds of formula IV A 1are treated with a halogenating agent under suitable conditions forgenerating halogen radicals, for example using N-bromo- orN-chlorosuccinimide in the presence of a free radical initiator such asAIBN to afford the compounds of formula 45. The halogen on the alphacarbon atom is then displaced by a nucleophile, for example an alkoxideto give the compounds of formula 51 or an amine to give the compounds offormula 46. The amine function is protected during synthesis byconverting it to the corresponding formamidine function affordingcompounds of formula 47. Compounds of formula 47 are reacted with analkoxymethylene malonate derivative of formula 8 in the presence of asuitably strong and hindered base, for example lithium diisopropylamide(LDA), preferably at a temperature below 0° C., and conveniently at -78°C. The formamidine group is then removed by reaction with hydrazine andacetic acid to afford the compounds of formula 48. The compounds offormula 48 are cyclized as discussed in reaction Scheme III, to affordthe compounds of formula 49. The leaving group, L, is then displaced asdiscussed in reaction Scheme III to afford the compounds of formula 50.The compounds of formula 50 are, in turn, converted to the compounds offormula V A1 as discussed in reaction Scheme I.

The compounds of formula 51 are converted to the compounds of formula VA2 by the following series of reactions: (1) reaction with analkoxymethylene malonate derivative of formula 8 in the presence of asuitably strong and hindered base, for example lithium diisopropylamide(LDA), preferably at a temperature below 0° C., and conveniently at -78°C., to afford the compounds of formula 52 (2) cyclization as discussedin reaction Scheme III, to afford the compounds of formula 53 (3)displacement of the leaving group in the 8-position as discussed inreaction Scheme III to afford the compounds of formula 54 and (4)conversion of the carboxylic acid ester to the corresponding carboxylicacids of formula V A2.

According to reaction Scheme V B illustrated above, compounds of formulaIV A2 are converted to compounds of formulae V B1 and V B2 by the sameprocedures discussed in reaction Scheme V A for the conversion ofcompounds of formula IV A1 to compounds of formulae V A1 and V A2.

According to reaction Scheme VI illustrated above, perfluoroinatedpyridine is converted to the compound of formula 66 by the proceduresdescribed in reaction Scheme IV A for the preparation of compounds offormula 33. Compounds of formula 66 are, in turn, converted to thecompounds of formula VI A and VI B by the series of reactions discussedin reaction Scheme III for the conversion of compounds of formula 23 tocompounds of formula III.

According to reaction Scheme VII illustrated above, compounds of formulaIV A2 are reacted with a protected alcohol of formula 71, in thepresence of a suitable base such as LDA, to afford compounds of formula72. The hydroxy protecting group is preferably a THP (tetrahydopyranyl)ether group. The compounds of formula 72 are, in turn, deprotected bystandard methods to afford the compounds of formula 73. The compounds offormula 73 are cyclized, in the presence of a suitable non-nucleophilicbase such as sodium hydride, to afford the compounds of formula 74. Thecompounds of formula 74 are then converted to the compounds of formula77 by the series of reactions described in reaction Scheme IV B for theconversion of the compounds of formula IV A3 to the compounds of formulaIV B.

Compounds of formula I, wherein R² contains a free primary amino groupare synthesized according to reaction Scheme VIII illustrated above. Inaccordance with reaction Scheme VIII, an alpha-halo acetate derivativeof formula 1, such as ethyl 2-fluoroacetate, is condensed with a formateester of formula 2, in the presence of a suitable base, for examplesodium ethoxide, in an inert solvent such as diethyl ether to give anenolate compound of formula 3. Compounds of formula 3 are, in turn,converted to compounds of formula 5 by condensation with an amidinederivative of formula 4, in the presence of a suitable base, for exampletriethylamine, in a polar solvent such as methanol. Thehydroxy-substituted compounds of formula 5 are converted to thecorresponding halo-derivatives of formula 6 by treatment with ahalogenating agent, for example phosphorus oxychloride to afford thechloro derivative, optionally in an inert solvent at a temperaturebetween about 20° C. and 145° C., depending on the halogenating agentand the boiling point of the solvent if one is used. When phosphorusoxychloride is the halogenating agent, the reaction temperature ispreferably between about 80° C. and 100° C. The leaving group in the5-position of the pyrimidine ring of compounds of formula 6 is thendisplaced by a nucleophile such as a nucleophilic amine, for exampleN-methylpiperazine or 2-methylpiperazine, to give the the compounds offormula 7. The reaction may be conducted at a temperature from about 20°C. to about 130° C. in a suitable organic solvent such as pyridine,methylene chloride, chloroform or 1-methyl-2-pyrrolidinone. It isdesirable to carry out the reaction in the presence of an acid-acceptorsuch as triethylamine, potassium carbonate and the like, at a molarratio of 1.0 to 2.0 moles of the acid acceptor per mole of compound ofthe formula 6. The amine can also be used as an acid acceptor in whichcase two or more equivalents of this reagent are used.

The compounds of formula 7 are reacted with an alkoxymethylene malonatederivative of formula 8 in the presence of a suitably strong hinderedbase, for example lithium diisopropylamide (LDA), preferably at atemperature below 0° C., and conveniently at -78° C. to afford thecompounds of formula 9. The compounds of formula 9 are cyclized in thepresence of a suitable hindered base, for example DBU, in an aproticsolvent, such as toluene, THF or chlorobenzene to give the compounds offormula 10. The cyclization is carried out at a temperature in the rangeof about 30° C. to about 130° C., preferably at the reflux temperture ofthe reaction mixture. The compounds of formula 10 are hydrolyzed in thepresence of a suitable base such as sodium or potasium hydroxide toafford the compounds of formula 78. The compounds of formula 78 are, inturn, chlorinated to afford the compounds of formula 10a using anappropriate chlorinating agent such as phosphorus oxychloride. Theleaving group in the 8-position of the quinolizinone compound of formula10a is then displaced using a nucleophilic amine such as3-aminopyrrolidine (with the primary amino group protected, for examplewith t-butoxycarbonyl). The protecting group is then removed to give thecompounds of formula 10b. The esters of formula 10b are then convertedto the carboxylic acids of formula I. The conversion may be achieved byconventional hydrolysis or by converting a compound of formula 10b tothe corresponding ester, via transesterification with an alcoholsuitable for selective hydrolysis, such as benzyl alcohol or2-(trimethylsilyl)ethanol (TMSE), in the presence of a catalyst, forexample titanium tetraethoxide, and then, in turn, removing the alcoholgroup by hydrogenolysis when R^(*) is benzyl or tetrabutylammoniumfluoride when R^(*) is TMSE to afford a compound of formula I.

Compounds of formula I where R³ is loweralkyl or halo(loweralkyl) aresynthesized according to reaction Scheme IX. In accordance with reactionScheme IX illustrated above, an alpha-halo acetate derivative of formula1, such as ethyl 2-fluoroacetate, is condensed with a compound offormula 78, where X may be a halogen or alkanoyl and R3 may beloweralkyl or halo(loweralkyl), for example acetyl chloride or ethyltrifluoroacetate, in the presence of a suitable base, for example sodiummethoxide or sodium ethoxide, and in a suitable solvent, such asmethanol, ethanol or ether, to give an alpha-fluoro beta-keto estercompound of formula 79. Compounds of formula 79 are then reacted withamidine compounds of formula 4 or formula 6, in which R¹ is an alkyl,halo(loweralkyl) or cycloalkyl group, or may be an electron withdrawinggroup such as phenyl, trifluoromethyl, cyano, perfluoroalkyl, vinyl,substituted vinyl, fluorine, nitro, acetylene, substituted acetylene,alkoxycarbonyl, or a nitrogen-containing aromatic heterocycle, in thepresence of a suitable base, such as sodium methoxide or sodiumethoxide, in the presence of a suitable solvent, such as methanol orethanol, to give compounds of formulae 81 or 80, respectively. Compoundsof formula 80 may be substituted for compounds of formula 8B in SchemeII and convened via the reactions in that Scheme, described above, intocompounds of formula I. Compounds of formula 81 may be substituted forcompounds of formula 5 in Scheme I and converted into compounds offormula I via the reactions of Scheme I described above. Alternatively,the compounds of formula 81 may be substituted for compounds of formula5 in Scheme VIII and convened via the reactions in that scheme,described above, into compounds of formula I.

Compounds of formula I where R² is loweralkyl, cycloalkyl, carbocyclicaryl(loweralkyl), cycloalkyl(loweralkyl), phenyl, nitrogen-containingaromatic heterocycle, or nitrogen-containing heterocycle are synthesizedaccording to reaction Scheme X. In accordance with reaction Scheme Xillustrated above, an organo-metallic derivative of formula 82, such asphenyl magnesium bromide, cyclopentyl magnesium bromide, orN-methylpiperidin-4-yl magnesium bromide is condensed with analpha-haloacetate derivative of formula 83, where X may be a halogen oralkoxy group, such as ethyl 2-fluoroacetate or 2-fluoroacetyl chloride,in an anhydrous solvent, for example ether or THF, to produce thealpha-fluoro compounds of formula 84. Compounds of formula 84, may inturn be reacted with a formate ester of formula 2, in the presence of asuitable base, for example sodium ethoxide, in an inert solvent such asdiethyl ether to give an enolate derivative of formula 85. The compoundsof formula 85 are in turn converted to compounds of formula 86 or 87 bycondensation with an amidine derivative of formula 4 or 6, in which R¹is loweralkyl, halo(loweralkyl) or cycloalkyl, or is an electronwithdrawing group such as phenyl, trifluoromethyl, cyano,perfluoroalkyl, vinyl, substituted vinyl, fluorine, nitro, acetylene,substituted acetylene, alkoxycarbonyl, or a nitrogen-containing aromaticheterocycle, in the presence of a suitable base, for exampletriethylamine, in a polar solvent such as methanol. Compounds of formula87 may be substituted for compounds of formula 7 in Scheme VIII, andconverted via the reactions in that scheme, described above, intocompounds of formula I. Compounds of formula 86 may be substituted forcompounds of formula 9B in Scheme II and, by reaction with a malonicacid diester as described for Scheme II above, convened directly intocompounds of formula 12B and, thence, into compounds of formula I.

Alternatively, compounds of formula I, where R² is loweralkyl,cycloalkyl, carbocyclic aryl(loweralkyl), cycloalkyl(loweralkyl),phenyl, nitrogen-containing aromatic heterocycle, or nitrogen-containingheterocycle are synthesized according to reaction Scheme XI. Analpha-haloacetate derivative of formula 1 is condensed with an acidhalide or ester derivative of formula 88, for example acetyl chloride,benzoyl chloride, isonicotinoyl chloride, or 2,6-dimethylisonicotinoylchloride, in an anhydrous solvent, for example ether, THF, anhydrousmethanol or an hydrous ethanol, in the presence of a suitable base, suchas sodium methoxide or NaN(TMS)2, to produce the beta-ketoesterderivative of formula 91, which is converted into compounds of formula92 in the presence of a suitable base, such as sodium methoxide orsodium ethoxide, in the presence of a suitable solvent, such asmethanol, ethanol or ether, to give the hydroxy-substituted compounds offormulae 92 or 93. These compounds, in turn, are converted into thecorresponding halo- derivatives of formulae 94 and 95 under conditionsas described for conversion of compounds of formula 5 to compounds offormula 6 in Scheme VIII. The compounds of formulae 94 and 95 are thenreacted with reducing agents such as zinc in acetic acid or hydrogen inthe presence of catalytic agents such as Ni, Pd, or Pt in suitablesolvents such as ethanol or methanol to produce the compounds of formula86 and 87, which are converted as described in Scheme X into compoundsof formula I.

In addition, the non-fluorinated derivatives of formula 90, where R2 isas described above, may be converted to the beta-ketoester derivativesof formula 91 using a reagent such as N-fluoropyridinium triflate,N-fluorosulfonyl amide, cesium fluorooxysulfate, or acetyl hypofluoride.

In accordance with Scheme XII, which illustrates a process for preparingthe desired compounds of formula Ib wherein R¹ is cyclopropyl,commercially available 3-chloro-2,4,5,6-tetrafluoropyridine (compound88) is reacted with an alkali salt of t-butanol, such as for example,sodium t-butoxide or lithium t-butoxide, in a polar organic solvent suchas THF, first at from 10° C. to -78° C. for 1-4 hours, then at roomtemperature for 2-72 hours, to give the compound of formula 89 (isolatedfrom a mixture of products by chromatography). The compound of formula89 is then reacted with hydrogen over a noble catalyst, such as Pd/C ina sodium acetate buffer, to remove the chlorine and give the compound offormula 90 (also isolated from a mixture of products by chromatography).In the instance where R⁶ is alkyl, the compound of formula 90 is thenreacted with a suitable alkyl halide, for example methyl halide or thelike, in the presence of a suitably strong and hindered base, forexample lithium diisopropylamide (LDA), preferably at a temperaturebelow 0° C., and conveniently at -78° C. to afford the compounds offormula 91. In the instance where R⁶ is haloalkyl, for examplefluoroalkyl, the compound of formula 90 is first reacted with a suitablystrong and hindered base, for example lithium diisopropylamide (LDA),preferably at a temperature below 0° C., and conveniently at -78° C.followed by reaction with formaldehyde to give the compound where R⁶ ishydroxymethyl which is then reacted with diaminosulfur trifluoride(DAST) in a non-polar solvent such as methylene chloride to give thecompound of formula 91. Alternately, when the R⁶ group is to be adifluoromethyl, for example, the compound of formula 90 is first reactedwith a suitably strong and hindered base, for example lithiumdiisopropylamide (LDA), preferably at a temperature below 0° C., andconveniently at -78° C. followed by reaction with DMF to form theintermediate compound wherein R⁶ is CHO, and this intermediate is thenreacted with DAST to prepare the compound of formula 91, wherein R6 isdifluoromethyl. The compounds of formula 91 are then reacted withhydrazine under nitrogen at reflux temperature for 2-8 hours, and afterremoval of excess hydrazine the residue is dissolved in an organicsolvent, such as methanol or benzene, for example, and air is thenpassed through the solution of the hydrazino product for 8-16 hours togive the compounds of formula 92. he compounds of formula 92 are thencondensed with cyclopropyl acetonitrile in a polar organic solvent, suchas THF, for example, in the presence of strong base, such as lithiumdiethylamide (LDA) or lithium diisopropylamide, at -78° C. for 1-4 hoursand then at 0° C. for 1-4 hours or NaNH2 at -5° C. to -10° C. for 1 to 8hours in order to prepare compounds of formula 93. The compounds offormula 93 are then reacted with trifluoroacetic acid under nitrogen for1-4 hours at ambient temperature to removed the protecting t-butoxidegroup, and the unprotected material is then reacted with POCl3 in asuitable organic solvent, such as DMF or methylene chloride, forexample, at ambient temperature for 8-24 hours in order to prepare thecompounds of formula 94.

In an improved preparative method, regarded as a part of the presentinvention, the compounds of formula 89 may be converted directly to thecompounds of formula 91 by treatment with a strong base, such ast-butyllithium or s-butyllithium, for example, in a polar solvent suchas THF or the like for a period of from 0.5 to 3 hours, followed byreaction with methyl iodide at a temperature firstly below -50° C. thenat ambient temperature for a period of from 4 to 20 hours. The compoundsof formula 91 may then be converted to the compounds of formula 92 bytreatment with a hydride reducing agent, such as LAH or sodiumbis-(2-methoxyethoxy)aluminum hydride (Red-Al™), for example, at from 0°C. to ambient temperature for a period of from 8-24 hours. The resultingcompounds of formula 93 are then reacted with POCl₃ in an organicsolvent such as DMF or methylene chloride, for example, at ambienttemperature for a period of from 6-20 hours in order to prepare directlythe compounds of formula 94.

The cyano compounds of formula 94 are converted to esters of formula 95by treatment with anhydrous ethanolic HCl followed by treatment with H₂O. The ester compounds of formula 95 are then reduced to the aldehydecompounds of formula 96 by reaction with lithium aluminum hydride in THFat reduced temperatures for 0.5-2 hours, followed by reaction withoxalyl chloride and DMSO in the presence of triethyl amine at -78° C.for 0.25-1.0 hours. The compounds of formula 96 are reacted with with amalonic acid diester, such as diethyl malonate, dibenzyl malonate,t-butyl malonate or di-t-butyl malonate, in the presence of a suitablebase such as piperidine and a catalytic amount of an acid, such asacetic acid or sulfuric acid, in a polar solvent, such as ethanol,followed by isolation of the intermediate compounds of formula 97 withsubsequent treatment thereof by heating in a polar, high-boiling solventsuch as DMF or DMSO at reflux temperature or in Dowtherm A™ for a periodof from 0.5 to 4 hours to form the pyridopyrimidine compounds of formula98. The chloro group of the compounds 98 is displaced as discussed inreaction Scheme I to afford the compounds of formula 99, which are inturn converted into the compounds of formula Ib as described in Scheme Ifor the conversion of compounds of formula 13A into compounds of formulaI.

In accordance with Scheme XIII, trifluoropyridine ether of formula 90 isreacted with a suitable strong base, for example, LDA, preferrably at atemperature below 0° C. and convenientyly at -78° C., in an inertsolvent such as THF, for example. The anion thus generated is thenreacted with an alkyl borate, such as, for example, trimethylborate ortriethylborate, followed by oxidation with hydrogen peroxide in thepresence of base such as sodium hydroxide in situ to give the compoundof formula 100, wherein R⁷ is lower alkyl. Compound 100 is thenalkylated with a suitable alkylating agent, such as an alkyl iodide oralkyl sulfate, for example methyl sulfate or ethyl iodide or the like,in the presence of a base such as sodium hydroxide, barium hydroxide,potassium carbonate, lithium carbonate, or the like, in a polar solvent,such as acetone, ethanol, DMF, THF, or the like, within a temperaturerange of room temperature to reflux temperature of the solvent, to givethe compound of formula 101. Alternately, compound 101 can be obtainedby treating compound 100 with an alcohol of the formula R⁷ OH, whereinR⁷ is as described above, triphenylphosphine and diethyldiazocarboxylatein a solvent such as THF at a temperature in the range of 0° C. to roomtemperture.

In accordance with Scheme XIV, commercially availablepentafluoropyridine of formula 102, is reacted with an alkali metal saltof t-butanol, for example, sodium t-butoxide or potassium t-butoxide, inan anhydrous organic solvent such as THF, at a temperature in the rangeof -78° C. to room temperature, to give the compound of formula 103.Compound 103 is then reacted with hydrazine at a temperature in therange of room temperature to reflux temperature, and in a solvent suchas methanol, iso-propanol, ether, or the like, followed by bubbling airthrough the solution of the intermediate in a solvent such as benzene oftoluene, in the presence of a base such as sodium hydroxide to give tocompound of formula 104.

In accordance with Scheme XV, the pentafluoropyridine of formula 102 isdissolved in a solvent, such as for example, THF or methylene chloride,and reacted with a cyclic amine of the formula R² H, wherein R² is asdefined above, or, when R² is substituted with a reactive group such asan amino group, a cyclic amine with suitably protected reactivesubstituents, in the presence iof a suitable base, such as a tertiaryamine, such as for example triethylamine, at a temperature in the rangeof 0° C. to room temperature. The reactant of formula 106, wherein R¹⁶is as defined above and TBS represents a tributylsilyl group, isgenerated from the corresponding iodide starting material by reactionwith t-butyl lithium in ether at -78° C., and is reacted with compound105 in a solvent such as THF or ether at -78° C. to give the compound offormula 107. The protecting TBS group is removed from compound 107 byreaction with tetrabutylammonium fluoride in THF at room temperature togive the compound of formula 108. The trifluoro compound 108 isconverted into the difluoro compound 109 by reacting compound 108 withhydrazine at reflux temperature in a solvent such as ether, propanol, ormethoxymethyl ether, followed by treatment of an intermediate hydrazinoproduct with CuSO4 in a solvent such as methanol, ethanol, or toluene,or alternately by reaction with air in the presence of a base such asNaOH. The monocyclic compound 109 is then converted into the bicycliccompound of formula 110 by reaction with NaH at reflux temperature in asolvent such as dioxane or THF. Compound 110 is then treated with astrong base, such as LDA at -78° C., for example, and condensed withdiethyl ethoxymethylenemalonate to give an intermediate product which iscyclized in the presence of a base such as DBU or piperidine/aceticacid, in a solvent such a ethanol or aqueous THF, at a temperature fromroom temperature to 60° C., to give the tricyclic ester of formula 111.The ester 111 is hydrolyzed to the acid of formula 112 with an alkalimetal hydroxide in aqueous THF, for example. Any protecting groupsremaining on the R2 or R16 groups may conveniently be removed at thispoint to give the desired compound of Formula I.

In accordance with Scheme XVI, an alternate method of preparingcompounds 112 is given. Compound 103 (from Scheme XIV) is reacted withcompound 106 (from Scheme XV) in a solvent such as THF or ether at -78°C. to give a TBS-protected intermediate compound, from which the TBSgroup is removed by reaction with tetrabutylammonium fluoride in THF atroom temperature to give the compound of formula 113. The trifluorocompound 113 is converted into the difluoro compound 114 by reactionwith hydrazine at reflux temperature in a solvent such as ether,propanol, or methoxymethyl ether, followed by treatment of anintermediate hydrazino product with CuSO4 in a solvent such as methanol,ethanol, or toluene, or alternately by reaction with air in the presenceof a base such as NaOH. The monocyclic compound 114 is then convertedinto the bicyclic compound of formula 115 by reaction with NaH at refluxtemperature in a solvent such as dioxane or THF. Compound 115 is thentreated with a strong base, such as LDA at -78° C., for example, andcondensed with diethyl ethoxymethylenemalonate to give an intermediateproduct which is cyclized in the presence of a base such as DBU orpiperidine/acetic acid, in a solvent such a ethanol or aqueous THF, at atemperature from room temperature to 60° C., to give the tricyclic esterof formula 116. The protecting t-butoxy group is removed from compounds116 by reaction with an acid, such as HCl or trifluoroacetic acid atroom temperature, and optionally in a suitable solvent, such asmethylene chloride or dioxane to give compound s 117. The free hydroxygroup of compounds 117 is then reacted with POCl3/DMF in a suitablesolvent such as methylene chloride at room temperature to give thechloro compounds of formula 118. Compounds 118 are reacted with a cyclicamine of the formula R² H, wherein R² is as defined above, or, when R²is substituted with a reactive group such as an amino group, a cyclicamine with suitably protected reactive substituents, in the presence ofa suitable base, such as a tertiary amine, such as for exampletriethylamine, in a suitable solven, such as acetonitrile or pyridine,at a reflux temperature to give the compounds 111. The ester group ishydrolyzed, and optional additional protecting groups removed, asdescribed in Scheme XV.

In accordance with Scheme XVII are prepared desired compounds of FormulaI wherein R⁵ is amino Compounds of formula 91 are reacted with HN-P,wherein P are amino protecting groups, for example benzyl andp-methoxybenzyl groups, in a solvent such as ethanol or toluene, atelevated temperature to give compounds of formula 119. Compounds offormula 119 are treated according to the procedures as described inSchemes XII, XV and XVI above to provide compounds of formula 120.Deprotection of protected amino compounds of formula 120 by catalytichydrogenation such as Pd-C in ethanol or methanol at room temperature,or by oxidation if R is p-methoxybenzyl with ammonium cerium nitrate,and the resulting compounds of formula 121 are hydrolyzed by a base suchas LiOH or NaOH to give compounds of formula 122.

In accordance with Scheme XVIII are prepared compounds of Formula Iwherein the R² group is a ring group attached via a carbon atom.Compounds of formula 123, wherein X is a leaving group such as chloride,bromide, iodide, fluoride or sulfonate, for example, is treated with anappropriately substituted malonate, wherein R, R' could be the same ordifferent) are alkyl groups, such as diethyl and di-t-butyl malonate, ina polar solvent such as DMF, DMSO, or the like, in the presence of astrong base such as NaH, at a temperature between 0° to 60° C., to givecompounds of formula 124. Decarboxylation of compounds of formula 124under acidic conditions, such as trifluoroacetic acid and hydrogenchloride in a solvent such as methylene chloride, ethanol, water, or thelike, followed by protection of the intermediate acid with an ester suchas diphenylmethyl ester by treating with diphenyl diazomethane in asolvent such as methylene chloride or THF, gives the compounds offormula 125. Compounds of formula 125 are then cyclized to compounds offormula 126 by reaction with Br(CH2)_(n) B(CH2)_(m) Br or I(CH2)_(n)B(CH2)_(m) I or R_(b) substituted iodide or bromide, for example,wherein B is CH₂, N, O or S, in the presence of a base such as NaH andin a solvent such as DMF, DMSO, or the like, at room temperature orelevated temperature. Alternately, conversion of compounds of formula125 to the methylenyl intermediate by reacting with aqueous formaldehydewith a base such as sodium bicarbonate in a solvent such as DMF,followed by reacting with methanesulfonyl chloride and triethylamine.The methylenyl compound is then converted to compound 126 by cyclizationor dipolar addition with a suitable reagent, such as trimethylsulfoniumiodide or diazomethane for cyclopropyl compound, in a solvent such asDMF, DMSO, or the like at 0° to 60° C. in the presence of a suitablebase such as NaH. Selective deprotection of the ester 'ROCO, such asusing trifluoroacetic acid and anisol at room temperature fordiphenylmethyl ester, followed by alkaline hydrolysis of the other esterprovides the desired compounds of formula 127, and followed by Curtiusrearrangement when 'R₂ is NH₂. In the compounds of formulas 126 and 127,n and m may be from 0-4, n+m=1-4, B may be CH₂, N, O or S; R^(b) may behydrogen, alkyl, amino, aminoalkyl, hydroxyl or alkoxyl groups, forexample, or other substituents as described for substituent Y insubformula Ib above.

Representative of the chemical intermediates which are useful in theabove syntheses, and which are regarded as a further aspect of thepresent invention, are the following compounds:

4-t-butoxy-3-chloro-2,5,6-trifluoropyridine;

4-t-butoxy-2,3,6-trifluoropyridine;

4-t-butoxy-2,3,6-trifluoro-5-methylpyridine;

4-t-butoxy-2,5-difluoro-3-methylpyridine;

2-(4-t-butoxy-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile;

2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile;

2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetic acid;

ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetate;

2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetaldehyde;

2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneethanol;

2-(2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylethylidinyl)-1,3-propanedicarboxylicacid, diethyl ester; and

8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4h-quinolizine-3-carboxylicacid ethyl ester.

The foregoing may be better understood from the following examples,which are presented for the purpose of illustration and are not intendedas a limitation upon the scope of the invention.

EXAMPLE 13-Fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

Step 1: 5-Fluoro-2-(4-fluorobenzyl)-4-hydroxypyrimidine

Sodium hydride (4.36 g of 60% NaH in mineral oil, 107.6 mmol) wassuspended, under a nitrogen atmosphere, in 125 mL of anhydrous diethylether in a 500 mL round-bottom flask fitted with a mechanical stirrer, athermometer and a condenser. To this mixture, with vigorous stirring,was slowly added 6.28 mL (107.6 mmol) of anhydrous ethyl alcohol. Afterthe evolution of gas ceased, a mixture of ethyl 2-fluoroacetate (10 mL,102.5 mmol) and ethyl formate (12.5 mL, 153.7 mmol) was added, dropwise,to the ethoxide solution. The reaction mixture was cooled when necessaryin order to maintain the reaction temperature between 18° C. and 20° C.The reaction mixture was stirred, under a nitrogen atmosphere, at18°-20° C. for 4.75 hours. The solvent was removed under aspiratorpressure, fresh anhydrous diethyl ether was added to the residue and theether solution was concentrated under reduced pressure to afford, as asolid residue, the sodium enolate of ethyl2-fluoro-3-oxo-2-propanecarboxylate, as described by E. Elkik and M.Imbeaux-Oudotte in Bull Soc Chim, 1165-1169, 1975. To this residue wasadded 20.3 g (107.6 mmol) of 4-fluorobenzylamidine hydrochloride,followed by 250 mL of methanol and 28.8 mL (205 mmol) of triethylamine(TEA). The reaction mixture was heated, with stirring, at refluxtemperature for 16 hours and then concentrated in vacuo. The residue wastriturated with hexane and the hexane was decanted. Water was added tothe residue and the aqueous mixture was acidified with glacial aceticacid and extracted with 4×150 mL of methylene chloride. The combinedorganic extract was washed with 200 mL of water and concentrated invacuo. The residue was recrystallized twice from ethyl acetatecontaining Norite® charcoal to afford the title compound, m.p. 169°-170°C.; MS DCI-NH₃ M/Z: 223 (M+H)⁺ ; ¹ H NMR (DMSO-d6) d 3.87 (s, 2H), 7.14(m, 2H), 7.33 (m, 2H), 7.98 (d, 1H). Analysis calculated for C₁₁ H₈ F₂N₂ O: C, 59.46; H, 3.63; N, 12.61. Found: C, 59.08; H, 3.70; N, 12.57.

Step 2: 4-Chloro-5-fluoro-2-(4-fluorobenzyl)-pyrimidine

A mixture of 1.93 g (8.7 mmol) of5-fluoro-2-(4-fluorobenzyl)-4-hydroxypyrimidine, from Step 1, and 15 mLof phosphorus oxychloride was heated in an oil bath at 90° C. for 1.5hours and then concentrated in vacuo. The residue was triturated with 75mL of ice water and the aqueous mixture was adjusted to pH 8-9 by theaddition of solid sodium bicarbonate. The mixture was extracted with3×70 mL of methylene chloride. The combined organic extracts were driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo toa light brown residue. The residue was purified by flash chromatographyon a 230-400 mesh silica gel column (4.8×14.6 cm) eluted withhexane:methylene chloride (1:1 v/v) to afford 1.94 g (90% yield) of thetitle compound; MS DCI-NH₃ M/Z: 241 (M+H)⁺ ; ¹ H NMR (CDCl₃) d 4.22 (s,2H), 7.00 (m, 2H), 7.30 (m, 2H), 8.48 (s, 1H).

Step 3:5-Fluoro-2-(4-fluorobenzyl)-4-(4-methylpiperazin-1-yl)-pyrimidine

A mixture of 0.48 g (2 mmol) of4-chloro-5-fluoro-2-(4-fluorobenzyl)-pyrimidine from Step 2 and 1.53 mL(14 mmol) of 4-methylpiperazine in 10 mL of methylene chloride wasstirred at ambient temperature for 1.5 hours. The reaction mixture wasconcentrated in vacuo and the residue was dissolved in methylenechloride. The resultant solution was washed with 4×30 mL of water, driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo togive 0.59 g (95% yield) of the title compound as an oil; ¹ H NMR (CDCl₃)d 2.32 (s, 3H), 2.47 (t, 4H), 3.78 (t, 4H), 3.99 (s, 2H), 6.97 (m, 2H),7.29 (m, 2H), 7.97 (d, 1H). The product was carded on to the next stepwithout purification.

Step 4: Diethyl2-ethoxy-3-(4-fluorophenyl)-3-[5-fluoro-4-(4-methypiperazin-1-yl)pyrimidin-2-yl]-propane-1,1-dicarboxylate

A solution of 0.35 mL (2.5 mmol) of diisopropylamine in 5 mL ofanhydrous tetrahydrofuran (THF) was prepared under a nitrogen atmosphereand cooled in an ice/water bath. To this solution was added via syringe,1.0 mL of a 2.5M solution of n-butyllithium (2.5 mmol) in hexane. Thesolution was stirred for 15 minutes at 0° C. and then cooled to -78° C.To the mixture at -78° C., was added a solution of 0.7 g (2.3 mmol) of5-fluoro-2-(4-fluorobenzyl)-4-(4-methylpiperazin-1-yl)-pyrimidine, fromStep 3, in 5 mL of anhydrous THF and a dark red-colored solution wasformed. The solution was stirred at -78° C. for 1 hour and then 0.46 mL(2.3 mmol) of ethyl 2-carboethoxy-3-ethoxy-2-propenecarboxylate wasadded. Stirring was continued at -78° C. for 3 hours and the reactionmixture turned a light yellow color. The reaction mixture was pouredinto 30 mL of water, with 6 g of solid ammonium chloride. The aqueousmixture was extracted with 4×50 mL of methylene chloride. The combinedorganic extract was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was dissolved in 300 mL of methylenechloride. The resultant solution was washed with a 50 mL portion ofwater, followed by a 75 mL portion of water, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to afford thetitle compound; MS DCI-NH₃ M/Z: 521 (M+H)⁺ ; ¹ H NMR (CDCl₃) d 0.84(2×t, 3H), 1.18 (t, 3H), 1.28 (t, 3H), 2.33 (s, 3H), 2.50 (m, 4H),3.36-3.53 (m, 2H), 3.83 (s, 4H), 3.96-4.22 (m, 4H), 4.42 (t, 1H), 4.98(dd, 1H), 6.95 (m, 2H), 7.48 (m, 2H), 7.99 (d, 1H).

Step 5: Ethyl3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate

A solution of 0.57 g (1.1 mmol) of diethyl2-ethoxy-3-(4-fluorophenyl)-3-[5-fluoro-4-(4-methypiperazin-1-ylpyrimidin-2-yl]-propane-1,1-dicarboxylate,from Step 4, and 0.2 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in200 mL of toluene was heated at reflux temperature, with stirring, for20.5 hours. During the first 0.5 hours, 125 mL of toluene was removedvia Dean Stark trap and 100 mL of fresh toluene was added through adropping funnel. Water (75 mL) was added to the reaction mixture andstirring was continued at ambient temperature for 3 hours. The organiclayer was separated and washed with 75 mL of water. The combined aqueouslayers were extracted with 3×75 mL of toluene. The organic layers wereall combined, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The residue (0.32 g) was purified on a 70-230mesh silica gel column (2.4×43 cm) eluted with ethyl alcohol:chloroform(1:10 v/v) to afford 0.26 g (56% yield) of the title compound, m.p.202°-204° C.; MS DCI-NH₃ M/Z: 429 (M+H)⁺ ; ¹ H NMR (CDCl₃) d 1.40 (t,3H), 2.33 (s, 3H), 2.51 (m, 4H), 3.93 (m, 4H), 4.40 (q, 2H), 7.08 (t,2H), 7.50 (m, 2H), 8.43 (s, 1H), 9.20 (d, 1H).

Step 6: Benzyl3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate

A mixture of 0.11 g (0.26 mmol) of ethyl3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate,from Step 5, 50 mL of dry benzyl alcohol and 0.05 mL of titaniumtetraethoxide was heated, with stirring, at 100° C. for 22 hours. Thebenzyl alcohol was removed by distillation under reduced pressure andthe residue was dissolved in 75 mL of methylene chloride. To thissolution was added 5 mL of saturated aqueous lithium fluoride solutionand the resultant mixture was stirred at ambient temperature for 20minutes. The layers were separated and the organic layer was dilutedwith 75 mL of methylene chloride and washed with 20 mL of water. Theaqueous layer was extracted with 25 mL of methylene chloride and themethylene chloride layer from this extraction was combined with theorganic layer. The combined organic layers were dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue (0.18 g) waschromatographed on a 70-230 mesh silica gel column (1.8×34 cm) elutedwith ethanol:chloroform (1:13 v/v) to afford 87 mg (67% yield) of thetitle compound; ¹ H NMR (CDCl₃) d 2.33 (s, 3H), 2.52 (m, 4H), 3.94 (m,4H), 5.40 (s, 2H), 7.08 (s, 2H), 7.27 (m, 5H), 8.44 (s, 1H), 9.21 (d,1H). The product was carded on to the next step without furtherpurification.

Step 7:3-Fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

Benzyl3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate(87 mg, 0.177 mmol), from Step 6, was dissolved in 20 mL of ethylacetate. To this solution was added 20 mg of 10% palladium on carbon andthe resultant mixture was hydrogenated at ambient temperature, under 4atmospheres of hydrogen, for approximately 19 hours. The catalyst wasremoved by filtration and washed with 400 mL of ethyl acetate Thefiltrate was concentrated in vacuo to give 65.2 mg of solid. The solidwas purified by chromatography on a 70-230 mesh silica gel column(1.8×18.5 cm) eluted with chloroform:methanol:acetic acid:water(100:25:5:2.5 v/v/v/v). The fractions containing the desired productwere combined and concentrated. Toluene was added to the residue andevaporated in vacuo. Chloroform was then added to the residue andevaporated in vacuo to afford the title compound as a yellow solid, m.p.225°-230° C.; MS DCI-NH₃ M/Z: 401 (M+H)⁺ ; ¹ H NMR (CDCl₃) d 1.68 (brs,1H), 2.33 (s, 3H), 2.53 (brs, 4H), 3.98 (brs, 4H), 7.10 (t, 2H), 7.48(m, 2H), 8.57 (s, 1H), 9.08 (d, 2H). Analysis calculated for C₂₀ H₁₈ F₂N₄ O₃ +0.75H₂ O: C, 58.03; H, 4.75; N, 13.54. Found: C, 57.98; H, 4.32;N, 13.22.

EXAMPLE 23-Fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

Step 1: Ethyl3-fluoro-9-(4-fluorophenyl)-2-hydroxy-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate

To a stirred solution of 0.87 g (2.05 mmol) of ethyl3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate,the product of Step 5 of Example 1, in 54 mL of THF/water (1:1) wasadded 6 mL of 1N aqueous sodium hydroxide solution. The reaction mixturewas stirred at ambient temperature for 6 hours and then was allowed tostand overnight at ambient temperature. The solid was filtered and driedto give the title compound; ¹ H NMR (d₆ -DMSO) d 1.23 (t, 3H), 4.15 (q,2H), 7.17 (m, 2H), 7.52 (m, 2H), 7.91 (s, 1H), 8.77 (d, 1H).

Step 2: Ethyl2-chloro-3-fluoro-9-(4-flourophenyl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate

A mixture of 55.7 mg of ethyl3-fluoro-9-(4-fluorophenyl)-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylatefrom Step 1 and 0.5 mL of phosphorus oxychloride was stirred and heatedat 90° C. for 1.25 hours. The mixture was evaporated under reducedpressure to yield the title compound which can be reacted with amineswithout purification. A pure sample of the title compound is obtained bytreatment of the crude product with aqueous sodium bicarbonate solutionand extracting the aqueous mixture with methylene chloride. The organicsolution is concentrated and chromatographed on silica gel eluting withethyl acetate.

Step 3: Ethyl3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate

Following the procedures described in Step 3 of Example 1, ethyl2-chloro-3-fluoro-9-(4-fluorophenyl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylatefrom Step 2 is reacted with 4-methylpiperazine to afford the titlecompound.

Step 4: Benzyl3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate

A mixture of 0.11 g (0.26 mmol) of ethyl3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate,from Step 3, 50 mL of dry benzyl alcohol and 0.05 mL of titaniumtetraethoxide was heated, with stirring, at 100° C. for 22 hours. Thebenzyl alcohol was removed by distillation under reduced pressure andthe residue was dissolved in 75 mL of methylene chloride. To thissolution was added 5 mL of saturated aqueous lithium fluoride solutionand the resultant mixture was stirred at ambient temperature for 20minutes. The layers were separated and the organic layer was dilutedwith 75 mL of methylene chloride and washed with 20 mL of water. Theaqueous layer was extracted with 25 mL of methylene chloride and themethylene chloride layer from this extraction was combined with theorganic layer. The combined organic layers were dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue (0.18 g) waschromatographed on a 70-230 mesh silica gel column (1.8×34 cm) elutedwith ethanol:chloroform (1:13 v/v) to afford 87 mg (67% yield) of thetitle compound; ¹ H NMR (CDCl₃) d 2.33 (s, 3H), 2.52 (m, 4H), 3.94 (m,4H), 5.40 (s, 2H), 7.08 (s, 2H), 7.27 (m, 5H), 8.44 (s, 1H), 9.21 (d,1H). The product was carried on to the next step without furtherpurification.

Step 5:3-Fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

Benzyl3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate(87 mg, 0.177 mmol), from Step 4, was dissolved in 20 mL of ethylacetate. To this solution was added 20 mg of 10% palladium on carbon andthe resultant mixture was hydrogenated at ambient temperature, under 4atmospheres of hydrogen, for approximately 19 hours. The catalyst wasremoved by filtration and washed with 400 mL of ethyl acetate Thefiltrate was concentrated in vacuo to give 65.2 mg of solid. The solidwas purified by chromatography on a 70-230 mesh silica gel column(1.8×18.5 cm) eluted with chloroform:methanol:acetic acid:water(100:25:5:2.5 v/v/v/v). The fractions containing the desired productwere combined and concentrated. Toluene was added to the residue andevaporated in vacuo. Chloroform was then added to the residue andevaporated in vacuo to afford the title compound as a yellow solid, m.p.225°-230° C.; MS DCI-NH₃ M/Z: 401 (M+H)⁺ ; ¹ H NMR (CDCl₃) d 1.68 (brs,1H), 2.33 (s, 3H), 2.53 (brs, 4H), 3.98 (brs, 4H), 7.10 (t, 2H), 7.48(m, 2H), 8.57 (s, 1H), 9.08 (d, 2H). Analysis calculated for C₂₀ H₁₈ F₂N₄ O₃ +0.75H₂ O: C, 58.03; H, 4.75; N, 13.54. Found: C, 57.98; H, 4.32;N, 13.22.

EXAMPLES 3-38

By following the procedures described in Example 2 and using theappropriate amine, Examples 3-20, as disclosed in Table 1, may beprepared which have the general formula ##STR17##

Likewise, Examples 21-38, as also disclosed in Table 1, may be preparedby using the appropriate amine and 2,4-difluorobenzylamidine instead of4-fluoro-benzylamidine to produce the general formula ##STR18##

                                      TABLE 1                                     __________________________________________________________________________    Example Nos.                                                                         R.sup.2    Example Nos.                                                                         R.sup.2                                              __________________________________________________________________________    3, 21                                                                                           12, 30                                                                                ##STR19##                                           4, 22                                                                                 ##STR20## 13, 31                                                                                ##STR21##                                           5, 23                                                                                 ##STR22## 14, 32                                                                                ##STR23##                                           6, 24                                                                                 ##STR24## 15, 33                                                                                ##STR25##                                           7, 25                                                                                 ##STR26## 16, 34                                                                                ##STR27##                                           8, 26                                                                                 ##STR28## 17, 35                                                                                ##STR29##                                           9, 27                                                                                 ##STR30## 18, 36                                                                                ##STR31##                                           10, 28                                                                                ##STR32## 19, 37                                                                                ##STR33##                                           11, 29                                                                                ##STR34## 20, 38                                                                                ##STR35##                                           __________________________________________________________________________     *The amines are protected and deprotected as described in Example 58     

EXAMPLE 399-Cyclopropyl-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

Step 1: 2-Cyclopropyl-3-hydroxyacrylic acid

A 1.1M solution of diethylzine (350 mL) in an oven-dried system underpositive nitrogen atmosphere is coled in an ice bath. Vinyl acetic acid(17 mL, 200 mmol) is added dropwise with stirring, followed by 24 mL(300 mmol) of diiodomethane. The reaction mixture is stirred overnightat ambient temperature. The reaction mixture is then cautiously pouredinto 500 mL of 1N aqueous hydrochloric acid solution and the aqueousmixture is extracted with diethyl ether. The organic layer is dried overanhydrous sodium sulfate, filtered and concentrated. The residue isvacuum distilled to give cyclopropylacetic acid.

The cyclopropylacetic acid (15 g, 150 mmol) in a flask protected frommoisture is cooled in an ice bath and 13.2 mL (180 mmol) of thionylchloride is added dropwise with stirring. After the addition iscomplete, the reaction mixture is warmed to ambient temperature and thento 50° C. The reaction mixture is heated at 50° C. for 1 hour and thencooled in an ice bath. Absolute ethanol (26 mL, 450 mmol) is addeddropwise with stirring to the reaction mixture. After the addition iscomplete, the reaction mixture is stirred at ambient temperatureovernight. The reaction mixture is diluted with 500 mL of methylenechloride and then washed with 200 mL of 5% aqueous sodium bicarbonatesolution. The organic layer is dried over anhydrous sodium sulfate,filtered and the ethyl ester of cyclopropylacetic acid is obtained bydistillation.

2-Cyclopropyl-3-hydroxyacrylic acid (12.8 g, 100 mmol), from Step 1, isdissolved in 150 mL of dry dimethoxyethane in an oven-dried system underpositive nitrogen atmosphere. The resultant solution is cooled in an icebath and 4.4 g of 60% sodium hydride in mineral oil is added. Themixture is stirred for several hours at approximately 0° C. and then forseveral hours at ambient temperature. The reaction mixture is cooled inan ice bath and 8.9 mL (110 mmol) of ethyl formate in 90 mL of drydimethoxyethane is added dropwise with stirring. After the addition iscomplete, the reaction mixture is stirred overnight at ambienttemperature. The reaction mixture is then cautiously poured into 300 mLof saturated aqueous ammonium chloride solution and extracted with ethylacetate. The ethyl acetate solution is dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to afford the titlecompound.

Step 2: Ethyl 5-Cyclopropyl-2,6-dihydroxy-nicotinic acid

A solution of 11.5 (88 mmol) of monoethyl malonate monoamide in 25 mL ofdry THF is cooled in an ice bath and is treated with 10.7 g (95 mmol) ofpotassium t-butoxide. The reaction mixture is stirred at 0°-5° C. for 1hour. A solution of 12.5 g (80 mmol) of 2-cyclopropyl-3-hydroxyacryllicacid, from Step 1, in 20 mL of dry THF is added dropwise with stirring.The reaction mixture is then warmed to ambient temperature and thenheated at reflux overnight. The reaction mixture is poured into brineand is extracted with ethyl acetate. The organic layer is dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to affordthe title compound.

Step 3: Ethyl 5-cyclopropyl-2,6-dichloro-nicotinic acid

Ethyl 5-cyclopropyl-2,6-dihydroxy-nicotinic acid (15.6 g, 70 mmol) fromStep 2, 1,2-dichloroethane (25 mL), anhydrous DMF (2 mL) and phosphorylchloride (14.3 mL, 150 mmol) are combined in a system under positivenitrogen atmosphere, The reaction mixture is stirred at ambienttemperature for 24 hours then diluted with 1,2-dichloroethane. Thereaction mixture is then washed with 5% aqueous sodium bicarbonatesolution and brine. The organic layer is dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to afford the titlecompound.

Step 4:2-Chloro-5-cyclopropyl-6-N-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)amino-nicotinicacid

Ethyl 5-Cyclopropyl-2,6-dichloro-nicotinic acid (11.2 g, 50 mmol) fromStep 3 is dissolved in 15 mL of anhydrous DMF. To this solution is added25 mL of concentrated ammonium hydroxide and the reaction mixture isheated at reflux overnight. The reaction mixture is cooled to ambienttemperature, diluted with water and extracted with 1,2-dichloroethane.The organic layer is dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue is dissolved in 250 mL of1,2-dichloroethane and 200 mL of 10% aqueous sodium carbonate solution.The reaction mixture is cooled in an ice bath and 16.5 g (60 mmol) of3,4-dimethoxy-6-nitrobenzylchloroformate is added. The reaction mixtureis stirred at 0°-5° C. for 1 hour. The layers are separated and theaqueous layer is extracted with 1,2-dichloroethane. The combined organiclayers are dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo.

Step 5:2-Chloro-5-cyclopropyl-6-N-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)-N-(2-fluoroacetyl)amino-nicotinicacid

2-Chloro-5-cyclopropyl-6-N-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)amino-nicotinicacid (14.4 g, 30 mmol) from Step 4 is dissolved in 20 mL of dry THF inan oven-dried system under positive nitrogen atmosphere. The reactionmixture is cooled in an ice bath and 1.3 g of 60% sodium hydride inmineral oil is added. The reaction mixture is stired at 0°-5° C. for 1hour and 3.2 g (33 mmol) of alpha-fluoroacetyl chloride in 5 mL of dryTHF is added dropwise with stirring. After the addition is complete, thereaction mixture is slowly warmed to ambient temperature and stirredovernight at ambient temperature. The reaction mixture is then pouredinto brine and extracted with ethyl acetate. The ethyl acetate solutionis dried over anhydrous sodium sulfate, filtered and concentrated invacuo. to afford the title compound.

Step 6:2-Chloro-5-cyclopropyl-6-N-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)-N-(2-fluoro-3-hydroxy-1-oxo-1-prop-2-enyl)amino-nicotinicacid

Sodium hydride ()880 mg of 60% NaH in mineral oil) is suspended in 10 mLof dry THF. The suspension is cooled in an ice bath and 10.7 g (20 mmol)of2-chloro-5-cyclopropyl-6-N-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)-N-(2-fluoroacetyl)amino-nicotinicacid, from Step 5, in 150 mL of dry THF is added dropwise with stirring.After the addition is complete, the reaction mixture is stirred at 0°-5°C. for 1 hour. Ethyl formate (1.78 mL, 22 mmol) in 25 mL of dry THF isadded dropwise with stirring. After the addition is complete, thereaction is stirred overnight at ambient temperature and then pouredinto 10% aqueous ammonium chloride solution. The aqueous mixture isextracted with ethyl acetate. The organic layer is dried over anhydroussodium sulfate, filtered and concentrated in vacuo to afford the titlecompound.

Step 7: Ethyl9-Cyclopropyl-1-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)3-fluoro-2-hydroxy-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate

A solution of 8.5 g (15 mmol) of2-Chloro-5-cyclopropyl-6-N-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)-N-(2-fluoro-3-hydroxy-1-oxo-1-prop-2-enyl)amino-nicotinicacid, from Step 6, is dissolved in 200 mL of dioxane/water (1:1). Tothis solution is added 4.1 g (30 mmol) of potassium carbonate. Thereaction mixture is heated at reflux with stirring overnight and thencooled to ambient temperature. The reaction mixture is then diluted withwater and extracted with ethyl acetate. The organic layer is dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to affordthe title compound.

Step 8: Ethyl9-cyclopropyl-3-fluoro-2-chloro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate

Ethyl9-cyclopropyl-1-((4,5dimethoxy-2-nitro-phenyl)methoxy-carbonyl)3-fluoro-2-hydroxy-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate(5.3 g, 10 mmol) from Step 7 is dissolved in 75 mL of 2:1 dioxane:waterand the resultant solution is illuminated with 320 nm light for 30 min.The reaction mixture is extracted with ethyl acetate. The organic layeris dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue is purified by silica gel chromatography to affordthe product of Step 7 with the nitrogen protecting group removed. Thisproduct is dissolved in 1,2-dichloroethane and tretaed with phosphorousoxychloride at ambient temperature for 18 hours. The reaction mixture isdiluted with 1,2-dichloroethane and is washed with saturated aqueoussodium bicarbonate solution and brine. The organic layer is dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to affordcrude title compound which is purified by recrystallization from ethylalcohol.

Step 9: Ethyl9-cyclopropyl-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

Following the procedures described in Step 3 of Example 1, ethyl9-cyclopropyl-3-fluoro-2-chloro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylatefrom Step 8 is reacted with 4-methylpiperazine to afford the titlecompound.

Step 10:9-cyclopropyl-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

Following the procedures described in Steps 5-7 of Example 1, Ethyl9-cyclopropyl-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid is converted to the title compound.

EXAMPLES 40-57

By following the procedures described in Example 39 and replacing4-methylpiperazine in Step 4 with the appropriate amine, Examples 40-57may be prepared as disclosed in Table 2 wherein the compounds have thegeneral formula ##STR36##

                                      TABLE 2                                     __________________________________________________________________________    Example No.                                                                          R.sup.2    Example No.                                                                          R.sup.2                                              __________________________________________________________________________    40                                                                                              49                                                                                    ##STR37##                                           41                                                                                    ##STR38## 50                                                                                    ##STR39##                                           42                                                                                    ##STR40## 51                                                                                    ##STR41##                                           43                                                                                    ##STR42## 52                                                                                    ##STR43##                                           44                                                                                    ##STR44## 53                                                                                    ##STR45##                                           45                                                                                    ##STR46## 54                                                                                    ##STR47##                                           46                                                                                    ##STR48## 55                                                                                    ##STR49##                                           47                                                                                    ##STR50## 56                                                                                    ##STR51##                                           48                                                                                    ##STR52## 57                                                                                    ##STR53##                                           __________________________________________________________________________     *The amines are protected and deprotected as described in Example 58     

EXAMPLE 58 8-(3-Amino-1-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Step 1: 4-Chloro-2-picoline

To 34.5 mL (0.37 mol) of phosphorus oxychloride, under a nitrogenatmosphere, was added 20.0 g (0.19 mol) of 2-picoline-N-oxide(commercially available from Aldrich Chemical Company) in smallportions. The reaction temperature slowly increased during the additionto ˜60° C. After the addition was complete, the reaction mixture was ahomogeneous dark red solution and the reaction temperature was 80° C.This solution was heated at 120° C. for 1.5 hours. The reaction mixturewas concentrated under reduced pressure in order to remove most of thephosphorus oxychloride and the concentrate was poured into ice water.The aqueous mixture was allowed to stand for 2 hours at ambienttemperature and then was extracted with diethyl ether. The ether extractwas discarded. The aqueous layer was adjusted to pH 8.0 with potassiumcarbonate and then extracted with ethyl acetate. The organic extract wasdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The liquid concentrate was distilled to afford 8.737 gof a mixture of the title compound and the isomeric 6-chloro-2-picolineas a clear colorless liquid, b.p. 70° C. (25 mm Hg). This product wascombined with another sample of the same mixture prepared separately bythe same procedure. The isomeric products were inseparable bydistillation. The combined products (12.905 g) were dissolved in 750 mLof ethyl alcohol. To the resultant solution was added, dropwise,concentrated nitric acid solution until a white precipitate formed andthe pH of the supernatant solution was 1. The precipitate was removed byfiltration and dissolved in water. The resultant aqueous solution wasadjusted to neutral pH with sodium bicarbonate and then extracted withmethylene chloride. The organic extract was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford7.487 g of the title compound. ¹ H NMR (CDCl₃) d 2.55 (s, 3H), 7.12 (dd,1H, J=3 Hz, 6 Hz), 7.18 (d, 1H, J=3 Hz), 8.40 (d, 1H, J=6 Hz).

Step 2: Diethyl2-ethoxy-3-(5-fluoropyridin-2-yl)-propane-1,1-dicarboxylate

Lithium diisopropylamide (LDA: 16 mL of a 1.5M solution in hexane) wasadded to 8 mL of dry THF, under a nitrogen atmosphere, and the resultantsolution was cooled to -70° C. in a isopropyl alcohol/dry ice bath. Tothe cooled solution of LDA, was added dropwise, over a 30 minute period,a solution of 2.5 g (19.6 mmol) of 4-chloro-2-picoline, from Step 1, in20 mL of dry THF. The solution turned a very dark red color. Afterstirring the dark red solution for 0.5 hours at -70° C., a solution of4.04 mL (19.6 mmol) of ethoxymethylenemalonate in 18 mL of dry THF wasadded dropwise over a 30 minute period. The reaction solution turnedfrom dark red to orange. After stirring for 0.5 hours at -70° C., thereaction solution was allowed to warm to -20° C. and was stirred at -20°C. for 1 hour. The reaction was quenched at -20° C. by the addition of1.3 mL of glacial acetic acid and the cooling bath was removed. After 20minutes the reaction solution was poured into 5% aqueous sodiumbicarbonate solution. The aqueous mixture was extracted with methylenechloride and the organic extract was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residue(8.03 g) was purified by chromatography on a silica gel column (˜120 gof SiO₂) eluted with 0.5% methanol in methylene chloride to afford 4.59g (68% yield) of the title compound.

Step 3: Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate

80 mL of Dowtherm A® in a 3-neck flask equipped with a thermometer, anaddition funnel and an air-cooled condenser was heated to 235° C., undernitrogen, using a heating mantel. A solution of 4.26 g (12.4 mmol) ofdiethyl 2-ethoxy-3-(5-fluoropyridin-2-yl)-propane-1,1-dicarboxylate,from Step 2, in 45 mL of Dowtherm A® was added, dropwise over a 1.5hours period, through the addition funnel to the heated stirringDowtherm A®. After the addition was complete, the resultant solution washeated at ˜200° C. for 1 hour and then was cooled to ambienttemperature. The black-green-colored solution was then poured into 500mL of hexane and a precipitate formed. The precipitate was collected byfiltration, washed with 5×100 mL of hexane and dried to afford 1.487 g(48% yield) of the title compound.

Step 4: Ethyl8-(3-(N-t-butoxycarbonyl)amino-1-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylate

Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (1.0 g, 3.97 mmol),from Step 3, was dissolved in 20 mL of dry pyridine under a nitrogenatmosphere. To the resultant solution was added a solution of 1.85 g(9.92 mmol) of 3-(N-t-butoxycarbonylamino)pyrrolidine in 5 mL of drypyridine and the reaction mixture was heated at 70° C. for 4.5 hours.The reaction mixture was then concentrated in vacuo in order to removeall of the pyridine. The dry residue (3.124 g) was purified bychromatography on silica gel eluted with 2% methanol in methylenechloride to afford 0.889 g (56% yield) of the title compound.

Step 5: 8-(3-Amino-1-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylic acidhydrochloride

A solution of 0.889 g (2.2 mmol) of ethyl8-(3-(N-t-butoxycarbonyl)amino-1-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylate,from Step 4, in 20 mL of trifluoroacetic acid (TFA) was stirred for 2hours at ambient temperature. The TFA was evaporated in vacuo and theresidue was dissolved in 200 mL of methanol. To the resultant solutionwas added 4.5 g of strongly basic ion exchange resin and the mixture wasstirred at ambient temperature for 1 hour. The mixture was filtered andthe filtrate was concentrated under reduced pressure to afford crudeethyl 8-(3-amino-1-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylate as aresidue. The residue was dissolved in 5 mL of THF and 11 mL of a 1Maqueous solution of sodium hydroxide was added. The reaction mixture washeated at 60° C. for 1 hour and then the reaction temperature wasincreased to 85° C. in order to evaporate the THF. The concentratedreaction solution was diluted with 20 mL of water and the pH of theresultant solution was adjusted to 1-2 with concentrated hydrochloricacid. The aqueous solution was concentrated in vacuo. The residue wascrystallized from ethyl alcohol:isopropyl alcohol:water (4:4:1 v/v/v)and recrystallized from ethyl alcohol/water to afford 0.388 g (57%yield) of the title compound, m.p.225°-230° C.; MS DCI-NH₃ : 274 (M-Cl)⁺90%, 230 ((M-Cl)-CO₂ H)⁺ base; IR (KBr): 3420 (OH), 1650 (C═O) cm⁻¹ ; ¹H NMR (TFA) d 2.8-3.1 (m, 6H), 4.62 (m, 1H), 7.06 (s, 1H), 7.4 (d, 2H,J=9 Hz), 8.14 (d, 1H, J=9 Hz), 9.06 (d, 1H, J=9 Hz). Analysis calculatedfor C₁₄ H₁₆ ClN₃ O₃ + 1/3H₂ O: C, 53.21; H, 5.10; N, 13.30. Found: C,53.58; H, 5.38; N, 13.30.

EXAMPLE 598-(3-(N-Norvalyl)amino-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylicacid

3-Amino-1-benzylpyrrolidine (I. Sumio and T. Matsuo, Japanese Kokai JP5328161, published Mar. 16, 1978) is coupled to N-t-butoxycarbonylnorvaline (Boc-nVal) using conventional N-hydroxysuccinimide couplingprocedures. The 1-benzyl group is removed by hydrogenolysis in methanolusing palladium on carbon catalyst. The3-(N-Boc-norvalyl)aminopyrrolidine is then reacted with ethyl8-chloro-4H-quinolizin-4-one-3-carboxylate, the product of Step 3 ofExample 58, as described in Step 4 of Example 58, replacing3-(N-t-butoxycarbonylamino)pyrrolidine with3-(N-Boc-norvalyl)aminopyrrolidine, to give8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylicacid with the nitrogen of the amino acid protected with a Boc group. TheBoc protecting group is removed by standard hydrolysis usingtrifluoroacetic acid and dilute aqueous hydrochloric acid.

Using the procedure outlined in Example 59, or any of the otherconventional condensation methods listed above, other amino acidderivatives of the compounds of this invention having an amino group canbe prepared. Examples of amino acids which can be coupled, either aloneor in combination with one and other, include naturally occurring aminoacids such as glycine, alanine, leucine, isoleucine, methionine,phenylalanine, valine, and the like, as well as synthetic amino acidssuch as cyclohexylalanine, cyclohexylglycine, aminopentanoic acid, andthe like.

EXAMPLE 60 8-Chloro-4-H-quinolizin-4-one-3-carboxylic acid

Step 1: Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate

35 mL of Dowtherm A® in a 3-neck flask equipped with a thermometer, anaddition funnel and an air-cooled condenser was heated to 230°-235° C.,under positive nitrogen pressure, using a heating mantel. A solution of2.7 g (7.85 mmol) of diethyl2-ethoxy-3-(5-fluoropyridin-2-yl)-propane-1,1-dicarboxylate, the productof Step 2 of Example 58, in 45 mL of Dowtherm A® was added, dropwiseover a 1.5 hours period, through the addition funnel to the heatedstirring Dowtherm A®. After the addition was complete, the resultantsolution was heated at ˜200° C. for 40 minutes and then was cooled toambient temperature. The black-green-colored solution was then pouredinto 600 mL of hexane and a precipitate formed. The precipitate wascollected by filtration, washed with 2×150 mL of hexane and dried toafford 1.15 g (58% yield) of the title compound, m.p. 153°-154° C.

Step 2: 8-Chloro-4-H-quinolizin-4-one-3-carboxylic acid

Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (125 mg, 0.5 mmol) wassuspended in 5 mL of 0.5N aqueous sodium hydroxide solution. Thereaction mixture was heated to 65° C. and 2 mL of THF was added. Afterthe reaction mixture was stirred at 65° C. for 1 hour, the THF wasdistilled from the mixture. Stirring was continued for 2 hours at 65° C.and then the reaction mixture was allowed to cool to ambienttemperature. The aqueous mixture was adjusted to pH 2 with 3 mL of 1.0Naqueous hydrochloric acid solution and diluted with 10 mL of water. Theprecipitate was collected by filtration, washed with 2×15 mL of waterand dried in vacuo to afford 100 mg (89% yield) of the title compound,m.p. 229°-230° C. The product was recrystallized from ethyl alcohol anddried in vacuo to afford 50 mg (44.5% yield) of the title compound, m.p.237°-238° C.; MS DCI-NH₃ : 224 (M+H)⁺, 241 (M+NH₄)⁺ ; IR (KBr): 3430(OH), 1740 (C═O) cm⁻¹ ; ¹ H NMR (CDCl₃) d 6.89 (d, 1H, J=6.9 Hz), 7.30(dd, 1H, J=2.1 Hz, J=6.6 Hz), 7.71 (d, 1H, J=2.1 Hz), 8.64 (d, 1H, J=6.9Hz), 9.25 (d, 1H, J=6.6 Hz). Analysis calculated for C₁₀ H₆ ClNO₃ : C,53.71; H, 2.70; N, 6.26. Found: C, 54.27; H, 2.86; N, 6.23.

EXAMPLE 61 8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Step 1: Ethyl8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylate

Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (755 mg, 3.0 mmol), theproduct of Step 3 of Example 58, was suspended in 12 mL of dry pyridineunder a nitrogen atmosphere. To the resultant solution was added 6.0 mL(6.0 mmol) of N-methylpiperazine and the reaction mixture was heated at70° C. for 8 hours. The reaction mixture was then concentrated in vacuoin order to remove all of the pyridine. The dry residue (3.124 g) wasdissolved in 125 mL of methylene chloride and the methylene chloridesolution was washed with 125 mL of saturated sodium chloride solution(brine). The aqueous layer was extracted with 125 mL of methylenechloride and the combined methylene chloride solutions were dried overanhydrous sodium sulfate, filtered and concentrated and dried in vacuoto afford 1.01 g of the title compound.

Step 2: 8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylic acidhydrochloride

A mixture of 0.865 g (2.75 mmol) of ethyl8-(4-methylpiperazin-l-yl)-4H-quinolizin-4-one-3-carboxylate, from Step1, in 12 mL of THF and 16.5 mL of a 0.5N aqueous solution of sodiumhydroxide was heated, with stirring, at 75° C. for 8 hours. The THF wasremoved from the reaction mixture by distillation during the reaction.The concentrated reaction mixture was cooled to ambient temperature andadjusted to pH 2.0 with 10.5 mL of 1N aqueous hydrochloric acidsolution. The aqueous solution was concentrated in vacuo to remove ˜80%of the water and the concentrate was diluted with 50 mL of 95% ethylalcohol. The solid was collected by filtration, washed with 2×5 mL ofethyl alcohol and dried in vacuo to afford the desired product. Theproduct was recrystallized from ethyl alcohol/water (3:1 v/v) to afford0.332 g (37% yield) of the title compound, m.p.257°-258° C.; MS DCI-NH₃: 288 (M-Cl)⁺ 90%, 244 ((M-Cl)-CO₂ H)⁺ base, 270 (M-Cl-H₂ O)⁺ ; IR(KBr): 3420 (OH), 1645 (C═O) cm⁻¹ ; ¹ H NMR (TFA) d 3.20 (m, 3H), 3.52(dd, 2H, J=10 Hz), 4.02 (m, 4H), 4.63 (d, 2H, J=12 Hz), 7.41 (m, 2H),7.65 (d, 1H, J=7.5 Hz), 8.26 (d, 1H, J=9 Hz), 9.18 (d, 1H, J=7.5 Hz).Analysis calculated for C₁₅ H₁₈ ClN₃ O₃ +0.5H₂ O: C, 54.14; H, 5.75; N,12.62. Found: C, 54.23; H, 5.54; N, 12.64.

EXAMPLE 628-(3-Amino-1-pyrrolidinyl)-1-ethyl-4H-quinolizin-4-one-3-carboxylic acidhydrochloride

Step 1: 4-Chloro-2-propyl-pyridine

A 1.5M solution of LDA in hexane (100 mL, 150 mmol) was cooled to -60°C. in an isopropyl alcohol/dry ice bath. To the stirred LDA solution,under nitrogen, was added, dropwise over a 0.5 hours period, a solutionof 17.466 g (137 mmol) of 4-chloro-2-picoline (the product of Step 1 ofExample 58) in 80 mL of dry THF. The reaction mixture was stirred for0.5 hours at -60° C. and then a solution of 10.95 mL (137 mmol) of ethyliodide in 30 mL of dry THF was added, dropwise over a 20 minute period.After the reaction mixture was stirred at -60° C. for 0.5 hours, thecooling bath was allowed to slowly (1.5 hours) warm to -30° C. Accordingto TLC analysis on silica gel eluted with 5% methanol in methylenechloride, the reaction had gone to completion. The reaction mixture waspoured into cold brine and the aqueous mixture was extracted withmethylene chloride. The organic extract was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was distilledto afford 12.667 g (60% yield of the title compound, b.p. 77°-80° C. (10mm Hg).

Step 2: Diethyl2-ethoxy-3-[4-chloro-2-pyridyl]-pentane-1,1-dicarboxylate

A solution of 12.6 mL (89.9 mmol) of diisopropylamine in 20 mL ofanhydrous tetrahydrofuran (THF) was prepared under a nitrogen atmosphereand cooled in an ice/water bath. To this solution was added, dropwiseover a 30 minute period, 36 mL of a 2.5M solution of n-butyllithium (90mmol) in hexane. The solution was stirred for 30 minutes at 0° C. andthen cooled to -60° C. To the amine solution at -60° C., was added,dropwise over a 30 minute period, a solution of 12.66 g (81.9 mmol) of4-chloro-2-propyl-pyridine, from Step 1, in 100 mL of anhydrous THF anda dark red-colored solution was formed. The solution was stirred at -60°C. for 0.5 hours and then 16.55 mL (81.9 mmol) of ethyl2-carboethoxy-3-ethoxy-2-propenecarboxylate was added, dropwise over a30 minute period. Stirring was continued at -60° C. for 0.5 hours and at-20° C. for 1.5 hours. The reaction mixture was poured into cold brineand the aqueous mixture was extracted with methylene chloride. Thecombined organic extract was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to afford 35.48 g of the titlecompound. The product was carried on to the next step withoutpurification.

Step 3: Ethyl 8-chloro-1-ethyl-4-H-quinolizin-4-one-3-carboxylate

A solution of 35.48 g (99.2 mmol) of diethyl2-ethoxy-3-[4-chloro-2-pyridyl]-pentane-1,1-dicarboxylate, from Step 2,in 1 L of xylene was heated at 150° C., with stirring, for 24 hours andthen concentrated in vacuo. The residue was washed with a mixture ofhexane and cyclohexane to afford 14.867 g (54% yield) of the titlecompound as a green solid; MS DCI-NH₃ M/Z: 280 (M+H)⁺, 246 (M-Cl)⁺, 217(MCl-Et)⁺ ; ¹ H NMR (CDCl₃) d 1.31 (t, 3H, J=7.5 Hz), 1.43 (t, 3H, J=7.2Hz), 2.78 (q, 2H, J=7.5 Hz), 4.43 (q, 2H, J=7.2 Hz), 7.10 (dd, 1H, J=2.4Hz, 8.1 Hz), 7.70 (d, 1H, J=2.4 Hz), 8.32 (s, 1H), 9.40 (d, 1H, 8.1 Hz).

Step 4: Ethyl8-(3-(N-t-butoxycarbonyl)amino-1-pyrrolidinyl)-1-ethyl-4H-quinolizin-4-one-3-carboxylate

Ethyl 8-chloro-1-ethyl-4H-quinolizin-4-one-3-carboxylate (1.20 g, 4.3mmol), from Step 3, was dissolved, under a nitrogen atmosphere, in 15 mLof dry pyridine. To the resultant solution was added 1.04 g (5.59 mmol)of 3-(N-t-butoxycarbonylaminopyrrolidine) and 1.8 mL (12.9 mmol) of drytriethylamine and the reaction mixture was heated at 60° C. for 12hours. The reaction mixture was then concentrated in vacuo in order toremove all of the pyridine. Ethyl alcohol (4 mL) was added to the dryresidue. The mixture was filtered to give 0.421 g of the desired productas a solid. The filtrate was concentrated and the residue purified byflash chromatography on silica gel eluted with 2% methanol in methylenechloride, followed by 5% methanol in methylene chloride to afford anadditional 1.273 g of the desired product. The title compound wasobtained in 92% yield (1.694 g) as a yellow solid and taken on to thenext step.

Step 5:8-(3-Amino-1-pyrrolidinyl)-1-ethyl-4H-quinolizin-4-one-3-carboxylic acidhydrocloride

A solution of 1.694 g (3.94 mmol) of ethyl8-(3-(N-t-butoxycarbonyl)-amino-1-pyrrolidinyl)-1-ethyl-4H-quinolizin-4-one-3-carboxylate,from Step 4, in 25 mL of trifluoroacetic acid (TFA) was stirred for 2hours at ambient temperature. The TFA was evaporated in vacuo and theresidue was dissolved in 200 mL of methanol. To the resultant solutionwas added 25 g of strongly basic ion exchange resin and the mixture wasstirred at ambient temperature for 2 hours. The mixture was filtered andthe filtrate was concentrated under reduced pressure to afford 1.146 g(88% yield) of ethyl8-(3-amino-1-pyrrolidinyl)-1-ethyl-4H-quinolizin-4-one-3-carboxylate asa residue. The residue was dissolved in 6 mL of THF and 10.5 mL of a 1Maqueous solution of sodium hydroxide was added. The reaction mixture washeated at 60° C. for 2 hours and then the reaction temperature wasincreased to 90° C. for 2 hours, in order to evaporate the THF. Theconcentrated reaction solution was poured into water and the pH of theresultant solution was adjusted to ˜2 with concentrated hydrochloricacid. The solid was filtered to afford 0.365 g (31% yield) of the titlecompound, m.p. 196°-198° C.; MS DCI-NH₃ : 302 (M-Cl)⁺ base, 258((M-Cl)-CO₂ H)⁺ 25%; IR (KBr): 3440 (OH), 2960, 1650 (C═O), 1500, 1360,1280 cm⁻ ; ¹ H NMR (TFA) d 1.41 (t, 3H, J=7.5 Hz), 2.39 (q, 2H, J=7.5),2.70 (m, 3H), 4.0 (m, 3H), 4.53 (m, 1H), 6.93 (d, 1H, J=1.5 Hz), 7.33(dd, 1H, J=9 Hz, 1.5 Hz), 7.93 (s, 1H), 9.08 (d, 1H, J=9 Hz). Analysiscalculated for C₁₆ H₂₀ ClN₃ O₃ : C, 56.98; H, 5.97; N, 12.44. Found: C,56.83; H, 6.00; N, 11.93.

EXAMPLE 638-(3-(Alanyl)amino-pyrrolidinyl)-1-ethyl-4H-quinolizin-4-one-3-carboxylicacid

3-Amino-1-benzylpyrrolidine (I. Sumio and T. Matsuo, Japanese Kokai JP5328161, published Mar. 16, 1978) is coupled to N-t-butoxycarbonylalanine (Boc-Ala) using conventional N-hydroxysuccinimide couplingprocedures. The 1-benzyl group is removed by hydrogenolysis in methanolusing palladium on carbon catalyst. The 3-(N-Boc-alanyl)aminopyrrolidineis then reacted with ethyl8-chloro-1-ethyl-4H-quinolizin-4-one-3-carboxylate, the product of Step3 of Example 62, as described in Step 4 of Example 62 replacing3-(N-t-butoxycarbonylaminopyrrolidine) with3-(N-Boc-alanyl)aminopyrrolidine, to give8-(3-(N-alanyl)amino-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylic acidwith the nitrogen of the amino acid protected with a Boc group. The Bocprotecting group is removed by standard hydrolysis using trifluoroaceticacid and dilute aqueous hydrochloric acid.

Using the procedure outlined in Example 63, or any of the otherconventional condensation methods listed above, other amino acidderivatives of the compounds of this invention having an amino group canbe prepared. Examples of amino acids which can be coupled, either aloneor in combination with one and other, include naturally occurring aminoacids such as glycine, alanine, leucine, isoleucine, methionine,phenylalanine, valine, and the like, as well as synthetic amino acidssuch as cyclohexylalanine, cyclohexylglycine, aminopentanoic acid, andthe like.

EXAMPLE 641-Ethyl-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylic acidhydrochloride

Step 1: Ethyl1-ethyl-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylate

Ethyl 8-chloro-1-ethyl-4H-quinolizin-4-one-3-carboxylate (558 mg, 2.0mmol), the product of Step 3 of Example 62, was dissolved in 10 mL ofdry pyridine under a nitrogen atmosphere. To the resultant solution wasadded 600 mg (6.0 mmol) of 2-methylpiperazine and the stirred reactionmixture was heated at 65° C. for 3 hours. The reaction mixture wasallowed to cool to ambient temperature and then concentrated in vacuo inorder to remove all of the pyridine. The residue was dissolved in 60 mLof methylene chloride and the methylene chloride solution was washedwith 60 mL of water. The aqueous layer was extracted with 2×60 mL ofmethylene chloride and the combined methylene chloride solutions weredried over anhydrous sodium sulfate, filtered and concentrated and driedin vacuo to afford 690 mg of the title compound. The product was carriedon to the next step without purification.

Step 2:1-Ethyl-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylic acidhydrochloride

To a suspension of 0.686 g (2 mmol) of ethyl1-ethyl-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylate,from Step 1, in 8 mL of THF was added 8.0 mL of a 1.0N aqueous sodiumhydroxide solution and the reaction mixture was heated, with stirring,at 65° C. for 3 hours. The THF was removed from the reaction mixture bydistillation during the reaction. The concentrated reaction mixture wascooled to ambient temperature and adjusted to pH 1-2 with 16 mL of 1Naqueous hydrochloric acid solution. The aqueous solution wasconcentrated in vacuo to remove the water and the residue was suspendedin 10 mL of water. The solid was collected by filtration and dried invacuo to afford the 385 mg (55% yield) of the title compound, m.p.>295°C.; MS DCI-NH₃ : 316 (M-Cl)⁺ ; IR (KBr): 3420 (OH), 1720 (C═O) cm⁻¹ ; ¹H NMR (TFA) d 1.50 (t, 3H, J=7.5 Hz), 1.70 (d, 3H, J=6 Hz), 3.00 (q, 2H,J=7.5 Hz), 3.70-4.10 (m, 6H), 4.55 (m, 1H), 4.60 (m, 1H), 7.40 (d, 1H,J=3.0 Hz), 7.68 (dd, 1H, J=3.0 Hz, 8.4 Hz), 8.18 (s, 1H), 9.19 (d, 1H,J=8.4 Hz). Analysis calculated for C₁₇ H₂₂ ClN₃ O₃ +H₂ O: C, 55.21; H,6.54; N, 11.36. Found: C, 55.19; H, 6.07; N, 11.34.

EXAMPLE 651-Ethyl-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylic acidhydrochloride

Step 1: Ethyl1-ethyl-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylate

Ethyl 8-chloro-1-ethyl-4H-quinolizin-4-one-3-carboxylate (279 mg, 1.0mmol), the product of Step 3 of Example 62, was dissolved in 5 mL of drypyridine under a nitrogen atmosphere. To the resultant solution wasadded 2 mL (2.0 mmol) of N-methylpiperazine and the stirred reactionmixture was heated at 85° C. for 2.5 hours. The reaction mixture wasallowed to cool to ambient temperature and then concentrated in vacuo inorder to remove all of the pyridine. The residue was dissolved in 50 mLof methylene chloride and the methylene chloride solution was washedwith 50 mL of 5% aqueous sodium bicarbonate solution. The aqueous layerwas extracted with 3×50 mL of methylene chloride and the combinedmethylene chloride solutions were dried over anhydrous sodium sulfate,filtered and concentrated and dried in vacuo to afford 343 mg of thetitle compound, m.p. 94°-96° C.; MS DCI-NH₃ : 344 (M+H)⁺.

Step 2:1-Ethyl-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylic acidhydrochloride

To a solution of 171 mg (0.5 mmol) of ethyl1-ethyl-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylate,from Step 1, in 4 mL of THF was added 4.0 mL of a 1.0N aqueous sodiumhydroxide solution and the reaction mixture was heated, with stirring,at 75° C. for 4.5 hours. The reaction mixture was cooled to ambienttemperature and adjusted to pH 2 with 5 mL of 1N aqueous hydrochloricacid solution. The aqueous solution was concentrated in vacuo to ˜5 mLand the solid was collected by filtration and dried in vacuo to afford120 mg (68% yield) of the title compound, m.p. 293°-294° C. (dec); MSDCI-NH₃ : 316 (M-Cl)⁺ 90%, 272 ((M-Cl)-CO₂ H)⁺ base; IR (KBr): 3420(OH), 1695 (C═O), 1640 (C═O) cm⁻¹ ; ¹ H NMR (TFA) d 1.47 (t, 3H, J=7.5Hz), 3.00 (q, 2H, J=7.5 Hz), 3.23 (s, 3H), 3.55 (dd, 2H, J=9 Hz), 4.12(m, 4H), 4.65 (d, 2H, J=15 Hz), 7.40 (s, 1H), 7.67 (d, 1H, J=9 Hz), 8.18(s, 1H), 9.20 (d, 1H, J=7.5 Hz). Analysis calculated for C₁₇ H₂₂ ClN₃ O₃: C, 56.59; H, 6.42; N, 11.64. Found: C, 56.86; H, 6.19; N, 11.60.

EXAMPLE 66 4-Chloro-5-fluoro-2-picoline

Step 1: 2-(5-Nitro-2-pyridyl)-1,3-propanedicarboxylate

Sodium hydride (20.2 g of NaH suspended in hexane, 0.504 mol) wassuspended, under a nitrogen atmosphere, in 600 mL of anhydrous THF in a3-neck 2 L round-bottom flask equiped with an addition funnel and amechanical stirrer. The suspension was cooled to 0° C. in an ice bath. Asolution of 71.8 mL (0.473 mol) of diethyl malonate in 60 mL ofanhydrous THF was added dropwise to the sodium hydride suspension over a1 hour period. After the addition and the evolution of hydrogen gas werecomplete, the reaction mixture was stirred for 20 min at 0° C. Asolution of 50 g (0.3 15 mol) of 2-chloro-5-nitropyridine in 150 mL ofanhydrous THF was added dropwise to the mixture, over a 25 min period.The ice bath was removed and the deep red-colored solution was stirredat ambient temperature for 48 hours. These procedures were repeated onthe same scale. The two solutions containing the product wereconcentrated to ˜500 mL and poured into a mixture of 1 L of 10% aqueoussodium bicarbonate solution and 1 L of brine. The aqueous mixture wasextracted with 3×500 mL of methylene chloride. The combined organicextract was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to a solid residue. The residue was crystallizedfrom ethyl alcohol and the crystals were washed with hexane to yield 140g (79% yield) of the title compound as a bright yellow solid; MS DCI-NH₃M/Z: 283 (M+H)⁺ base, 253 ((M+H)-C₂ H₅)⁺ base; ¹ H NMR (CDCl₃) d 1.30(t, 6H, J=7.5 Hz), 4.26 (q, 2H, J=6.0 Hz), 4.29 (q, 2H, J=6.0 Hz), 5.08(s, 1H), 7.77 (dd, 1H, J=9.0 Hz, 0.6 Hz), 8.49 (dd, 1H, J=3.0 Hz, 9.0Hz), 9.38 (dd, 1H, J=3.0 Hz, 9.0 Hz).

Step 2: 5-Nitro-2-picoline

A suspension of 102.0 g (0.361 mol) of2-(5-nitro-2-pyridyl)-1,3-propanedicarboxylate, from Step 1, in 600 mLof 20% aqueous sulfuric acid solution was heated at 95° C. for 24 hours.The resultant solution was poured onto 1 kg of ice and the aqueousmixture was adjusted to a pH within the range pH 10-12 with 50% aqueoussodium hydroxide solution. The precipitate was filtered and dissolved inethyl acetate. The ethyl acetate solution was dried over anhydroussodium sulfate, filtered and concentrated to a solid residue. Theresidue was washed with hexane. The hexane was removed by filtration andthe solid was dried to afford 45.86 g (92% yield) of the title compound;¹ H NMR (CDCl₃) d 2.71 (s, 3H), 7.36 (d, 1H, J=9.0 Hz), 8.37 (dd, 1H,J=3.0 Hz, 9.0 Hz), 9.33 (d, 1H, J=3.0 Hz).

Step 3: 5-Amino-2-picoline

The product of Step 2, 5-nitro-2-picoline (45.86, 0.332 mol), wasdissolved in 200 mL of methanol and 1.15 g of 10% palladium on carbonwas added to the resultant solution. The reaction mixture washydrogenated at ambient temperature under 4 atmospheres of hydrogen. Thepalladium catalyst was removed by filtration through a 45μ Millipore®filter and the filtrate was concentrated in vacuo to afford 33.96 g (95%yield) of the title compound as a tan solid; ¹ H NMR (CDCl₃) d 2.42 (s,3H), 3.54 (brs, 2H), 6.91 (m, 2H), 8.00 (m, 1H).

Step 4: 5-Fluoro-2-picoline

A solution of 5-amino-2-picoline (20 g, 0.185 mol), from Step 3, in 105mL of ethyl alcohol was cooled to 0° C. Tetrafluoroboric acid (55 mL ofa 48% solution in water) was added to the cold 5-aminopicoline solutionand the flask containing the resultant solution was weighed. Ethylnitrite was bubbled through the cold solution until 13.88 g (0.185 mol)had been added. The addition took place over a 1.25 hours period. Afterthe addition was complete the reaction solution was allowed to sit at 0°C. for 15 min, during which time, the excess ethyl nitrite evaporatedfrom the solution. Diethyl ether (120 mL) was added to the reactionmixture to ensure complete precipitation of the tetrafluoroborate salt.After 30 minutes at 0° C., the mixture was filtered. The filter cake waswashed with 200 mL of diethyl ether, followed by 300 mL of hexane. Thesolid was transferred to a 1 L beaker containing approximately 300 mL ofhexane and 10.75 g (0.185 mol) of potassium fluoride. The mixture washeated to 40° C. over a 4.5 hours period. The orange-colored solid wasconverted to a black oily solid. The hexane was decanted and the residuewas cooled to 0° C. The cold residue was triturated with approximately200 mL of 50% sodium hydroxide. The mixture was combined with materialobtained from duplicate runs of the preceeding procedures and thecombined aqueous mixtures were steam distilled. The aqueous distillatecollected between 92° C. and 100° C. was extracted with two portions ofmethylene chloride. The combined methylene chloride extract was driedover anhydrous sodium sulfate, filtered and added to the (hexane)distillate which was collected between 62° C. and 65° C. The product wascarried on to the next step in solution.

Step 5: 5-Fluoro-2-picoline-N-oxide

To the solution of 5-fluoro-2-picoline obtained in Step 4, at 0° C., wasadded, with vigorous stirring, a cold solution of 40% peracetic acid(prepared by carefully adding 50 mL of 30% hydrogen peroxide solution to150 mL of glacial acetic acid). The reaction mixture was heated atreflux temperature (50° C.) for 4 days and then poured into 600mL of icewater. The aqueous mixture was adjusted to pH 9 by the addition ofpotassium carbonate and then was stirred at ambient temperature for 4hours. The aqueous solution was continuously extracted with methylenechloride for 24 hours and the methylene chloride extract was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to afford30.8 g (22% yield) of the title compound; MS DCI-NH₃ M/Z: 128 (M+H)⁺base; ¹ H NMR (CDCl₃) d 2.48 (s, 3H), 7.00 (ddd, 1H), 7.22 (dd, 1H),8.22 (dd, 1H).

Step 6: 5-Fluoro-4-nitro-2-picoline-N-oxide

The reaction was carried out in a flask vented to a gas scrubbercontaining aqueous sodium hydroxide solution. The product of Step 5,5-fluoro-2-picoline-N-oxide (1.0 g, 7.86 mmol) was cooled to 0° C. andconcentrated sulfuric acid (4.2 mL) was slowly added, with stirring.Solid potassium nitrate (1.27 g, 12.5 mmol) was then added to thismixture at 0° C., in small portions over a 45 minute period. Thereaction mixture was allowed to warm to ambient temperature and wasstirred at ambient temperature for 1 hour. Not all of the potassiumnitrate had dissolved and the reaction mixture was heated at 50° C. for0.5 hours and then at 100° C. for 18 hours. The homogeneous reactionsolution was poured over ice and the resultant aqueous solution wasadjusted to pH 9 with solid potassium carbonate. The aqueous solutionwas then extracted with 3×80 mL of methylene chloride. The combinedorganic extract was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give 1.084 g (80% yield) of the title compoundas a yellow solid, m.p. 107°-108° C.; MS DCI-NH₃ M/Z: 190 (M+NH₄)⁺ 10%,173 (M+H)⁺ 30%, 157 (M-O)⁺ 50%; ¹ H NMR (CDCl₃) d 2.48 (s, 3H), 8.05 (d,1H, J=9.0 Hz), 8.31 (d, 1H, J=6.0 Hz).

Step 7: 4-Chloro-5-fluoro-2-picoline-N-oxide

The product of Step 6, 5-fluoro-4-nitro-2-picoline-N-oxide (3.56 g, 20.6mmol) was dissolved in 30 mL of concentrated (37.5%) aqueoushydrochloric acid. The resultant solution was heated, with stirring, at110° C. for 48 hours and then concentrated in vacuo. Water (30 mL) wasadded to the residue and the resultant aqueous solution was adjusted topH 9-10 with sodium carbonate. The aqueous solution was then extractedwith 3×50 mL of methylene chloride and the combined organic extract wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The product was crystallized from hexane to afford 1.8 g (55% yield) ofthe title compound, m.p. 92°-93° C.; MS DCI-NH₃ M/Z: 179 (M+NH₄)⁺ 30%,162 (M+H)⁺ base, 146 (M-O)⁺ 60%; ¹ H NMR (CDCl₃) d 2.46 (s, 3H), 7.30(d, 1H, J=9.0 Hz), 8.26 (d, 1H, J=4.5 Hz); IR (chloroform solution) 1605(N-0), 1180 (C-F) cm⁻¹. Analysis calculated for C₆ H₅ ClFNO: C, 44.61;H, 3.12; N, 8.62. Found: C, 44.89; H, 3.25; N, 9.40.

Step 8: 4-Chloro-5-fluoro-2-picoline

4-Chloro-5-fluoro-2-picoline-N-oxide (12.43 g, 76.93 mmol), from Step 7,was dissolved in 52 mL of glacial acetic acid in a 3-necked flaskequiped with a mechanical stirrer, a condenser and a thermometer. Ironpowder (6.45 g, 115.5 mmol) was added to the solution at ambienttemperature and the reaction mixture was carefully heated to 35°-40° C.After 10 min at 30° C., an exothermic reaction took place which causedthe reaction temperature to rise to 120° C. and the reaction mixturebecame a very dark brown-colored solution. The flask was transferred toa cold water bath and the temperature of the solution brought down toambient. The reaction mixture was then poured over ice. The resultantaqueous mixture was adjusted to pH 9 with potassium carbonate and steamdistilled. The aqueous distillate collected at 92°-96° C. was extractedwith three portions of methylene chloride. The combined organic extractwas dried over anhydrous sodium sulfate, filtered and distilled toafford 15.91 g (71% yield) of the title compound, b.p. 138°-140° C.; MSGC-MS M/Z:146 (M+H)⁺ ; ¹ H NMR (CDCl₃) d 2.53 (s, 3H), 7.23 (d, 1H,J=6.0 Hz), 8.37 (s, 1H).

EXAMPLE 67 3,4-Dichloro-5-fluoro-2-picoline

To 0.87 g (6 mmol) of 4-chloro-5-fluoro-2-picoline, the product ofExample 66, in 20 mL of chloroform cooled to -45° C., is added 0.75 mLof t-butylhypochlorite. The reaction mixture is stirred at -45° C. for 2hours and at 0° C. for 2 hours. The reaction mixture is then poured intowater and the resultant aqueous mixture is extracted with methylenechloride. The organic solution is dried over anhydrous magnesiumsulfate, filtered, concentrated under reduced pressure and distilled toafford the title compound.

EXAMPLE 68 3-Bromo-4-chloro-5-fluoro-2-picoline

4-Chloro-5-fluoro-2-picoline, the product of Example 66, is treated withbromine in fuming sulfuric acid containing 65% sulfur trioxide for 7hours at 80° C. as described by L. van der Does and H. J. Hertog in RecTrav Chim 81:864 (1965) to afford the title compound.

EXAMPLE 69 4-Chloro-3,5-difluoro-2-picoline

4-Chloro-5-fluoro-2-picoline is treated with 1.1 equivalents of acetylhypofluorite as described by O. Lerman, et al. J Org Chem, 49:806-813(1984) to afford the title compound.

EXAMPLE 70 4-Chloro-5-fluoro-2-propyl-pyridine

Diisopropylamine (924 μL, 6.59 mmol) was dissolved in 9 mL of dry THFand the resultant solution was cooled to 0° C. in an ice bath.n-Butyllithium (3.07 mL of a 2.05M solution in THF, 6.29 mmol) was addedvia syringe to the amine solution and the resultant solution was stirredfor 30 minutes at 0° C. The lithium diisopropylamide (LDA) solution wasthen cooled to -50° C. in an isopropyl alcohol/dry ice bath. To the coldLDA solution was added, dropwise from an addition funnel, over a 15 minperiod, a solution of 4-chloro-5-fluoro-2-picoline (435 μL, 3.0 mmol),the product of Example 64, in 9 mL of THF. The reaction solution turneddark orange-brown in color. The reaction solution was stirred at atemperature in the range -50° C. to -45° C. for 5 hours and then wascooled over a 15 min period to -78° C. Ethyl iodide (792 μL, 9.9 mmol)was added in one portion and the reaction solution was stirred at -78°C. for 20 min. The reaction was then quenched by pouring the reactionsolution into 60 mL of 10% aqueous ammonium chloride solution. Theaqueous mixture was extracted with 2×50 mL of methylene chloride. Thecombined organic extract was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo and the residue was distilledtoafford the title compound, b.p. 80°-82° C. (12 mm Hg); MS DCI-NH₃ M/Z:174 (M+H)⁺ 40%; ¹ H NMR (CDCl₃) d 0.96 (t, 3H, J=7.5 Hz), 1.73 (spt, 2H,J=7.5 Hz), 2.73 (t, 2 H, J=7.5 Hz), 7.21 (d, 1H, J=6.0 Hz), 8.38 (s,1H).

EXAMPLE 71 3,4- Dichloro-5-fluoro2-propyl-pyridine

By following the procedures described in Example 67 and replacing4-chloro-5-fluoro-2-picoline (the product of Example 66) with4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70), thetitle compound can be prepared.

EXAMPLE 72 3-Bromo-4-chloro-5-fluoro-2-propyl-pyridine

By following the procedures described in Example 68 and replacing4-chloro-5-fluoro-2-picoline (the product of Example 66) with4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70), thetitle compound can be prepared.

EXAMPLE 73

4-Chloro-3,5-difluoro-2-propyl-pyridine

By following the procedures described in Example 69 and replacing4-chloro-5-fluoro-2-picoline (the product of Example 66) with4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70), thetitle compound can be prepared.

EXAMPLE 741-Ethyl-7-fluoro-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

By following the procedures described in Step 2 of Example 62 and inExample 65 and replacing 4-chloropicoline with4-chloro-5-fluoro-picoline (the product of Example 66), the titlecompound can be prepared.

EXAMPLE 751-Ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

By following the procedures described in Step 2 of Example 62 and inExample 65 and replacing 4-chloropicoline with4-chloro-5-fluoro-picoline (the product of Example 66), and replacingN-methylpiperazine with 2-methylpiperazine, the title compound can beprepared.

EXAMPLE 768-(3-Amino-1-pyrrolidinyl)-1-ethyl-7-fluoro-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Example 62, replacing4-chloropicoline with 4-chloro-5-picoline (the product of Example 66),the title compound is prepared.

EXAMPLE 779-Chloro-1-ethyl-7-fluoro-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Step 2 of Example 62 and inExample 65, replacing 4-chloropicoline with3,4-dichloro-5-fluoro-picoline (the product of Example 67), the titlecompound is prepared.

EXAMPLE 789-Chloro-1-ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Step 2 of Example 62 and inExample 65, replacing 4-chloropicoline with3,4-dichloro-5-fluoropicoline (the product of Example 67), and replacingN-methylpiperazine with 2-methylpiperazine, the title compound isprepared.

EXAMPLE 798-(3-Amino-1-pyrrolidinyl)-9-chloro-1-ethyl-7-fluoro-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Example 62, replacing4-chloropicoline with 3,4-dichloro-5-fluoropicoline (the product ofExample 67), the title compound is prepared.

EXAMPLE 809-Bromo-1-ethyl-7-fluoro-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Step 2 of Example 62 and inExample 65, replacing 4-chloropicoline with3-bromo-4-chloro-5-fluoropicoline (the product of Example 68, the titlecompound is prepared.

EXAMPLE 819-Bromo-1-ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Step 2 of Example 62 and inExample 65, replacing 4-chloropicoline with3-bromo-4-chloro-5-fluoro-picoline (the product of Example 68), andreplacing N-methylpiperazine with 2-methylpiperazine, the title compoundis prepared.

EXAMPLE 828-(3-Amino-1-pyrrolidinyl)-9-bromo-1-ethyl-7-fluoro-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Example 62, replacing4-chloropicoline with 3-bromo-4-chloro-5-fluoro-picoline (the product ofExample 68), the title compound is prepared.

EXAMPLE 837,9-Difluoro-1-ethyl-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Step 2 of Example 62 and inExample 65, replacing 4-chloropicoline with4-chloro-3,5-difluoropicoline (the product of Example 69), the titlecompound is prepared.

EXAMPLE 847,9-Difluoro-1-ethyl-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Step 2 of Example 62 and inExample 65, replacing 4-chloropicoline with4-chloro-3,5-difluoropicoline (the product of Example 69), and replacingN-methylpiperazine with 2-methylpiperazine, the title compound isprepared.

EXAMPLE 858-(3-Amino-1-pyrrolidinyl)-7,9-difluoro-1-ethyl-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Example 62, replacing4-chloropicoline with 4 -chloro-3,5-difluoropicoline (the product ofExample 69), the title compound is prepared.

EXAMPLE 861-Cyclopropyl-7-fluoro-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Steps 1 and 2 of Example 62 and inExample 65, replacing 4-chloropicoline with 4-chloro-5-fluoropicoline(the product of Example 66), and replacing ethyl iodide with cyclopropyliodide, the title compound is prepared.

EXAMPLE 871-Cyclopropyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Steps 1 and 2 of Example 62,replacing 4-chloropicoline with 4-chloro-5-fluoropicoline (the productof Example 66) and replacing ethyl iodide with cyclopropyl iodide, andthe procedures described in Example 65, replacing N-methylpiperazinewith 2-methylpiperazine, the title compound is prepared.

EXAMPLE 888-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Example 62, replacing4-chloropicoline with 4-chloro-5-fluoropicoline (the product of Example66), and replacing ethyl iodide with cyclopropyl iodide, the titlecompound is prepared.

EXAMPLE 899-Chloro-1-cyclopropyl-7-fluoro-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Steps 1 and 2 of Example 62,replacing 4-chloropicoline with 3,4-dichloro-5-fluoropicoline (theproduct of Example 67) and replacing ethyl iodide with cyclopropyliodide, and the procedures described in Example 65, the title compoundis prepared.

EXAMPLE 909-Chloro-1-cyclopropyl-7-fluoro-8-(3-methyl-1-piperazinyl-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Steps 1 and 2 of Example 62,replacing 4-chloropicoline with 3,4-dichloro-5-fluoropicoline (theproduct of Example 67) and replacing ethyl iodide with cyclopropyliodide, and the procedures described in Example 65, replacingN-methylpiperazine with 2-methylpiperazine, the title compound isprepared.

EXAMPLE 918-(3-Amino-1-pyrrolidinyl)-9-chloro-1-cyclopropyl-7-fluoro-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Example 62, replacing4-chloropicoline with 3,4-dichloro-5-fluoropicoline (the product ofExample 67) and replacing ethyl iodide with cyclopropyl iodide, thetitle compound is prepared.

EXAMPLE 929-Bromo-1-cyclopropyl-7-fluoro-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Steps 1 and 2 of Example 62,replacing 4-chloropicoline with 3-bromo-4-chloro-5-fluoropicoline (theproduct of Example 68) and replacing ethyl iodide with cyclopropyliodide, and the procedures described in Example 65, the title compoundis prepared.

EXAMPLE 939-Bromo-1-cyclopropyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Steps 1 and 2 of Example 62,replacing 4-chloropicoline with 3-bromo-4-chloro-5-fluoropicoline (theproduct of Example 68) and replacing ethyl iodide with cyclopropyliodide, and the procedures described in Example 65, replacingN-methylpiperazin with 2-methylpiperazine, the title compound isprepared.

EXAMPLE 948-(3-Amino-1-pyrrolidinyl)-9-bromo-1-cyclopropyl-7-fluoro-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Example 62, replacing4-chloropicoline with 3-bromo-4-chloro-5-fluoropicoline (the product ofExample 68) and replacing ethyl iodide with cyclopropyl iodide, thetitle compound is prepared.

EXAMPLE 951-Cyclopropyl-7,9-difluoro-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Steps 1 and 2 of Example 62,replacing 4-chloropicoline with 4-chloro-3,5-difluoropicoline (theproduct of Example 69) and replacing ethyl iodide with cyclopropyliodide, and the procedures described in Example 65, the title compoundis prepared.

EXAMPLE 961-Cyclopropyl-7,9-difluoro-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Steps 1 and 2 of Example 62,replacing 4-chloropicoline with 4-chloro-3,5-difluoropicoline (theproduct of Example 69) and replacing ethyl iodide with cyclopropyliodide, and the procedures described in Example 65, replacingN-methylpiperazine with 2-methylpiperazine, the title compound isprepared.

EXAMPLE 978-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-7,9-difluoro-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Following the procedures described in Example 62, replacing4-chloropicoline with 4-chloro-3,5-difluoropicoline (the product ofExample 69) and replacing ethyl iodide with cyclopropyl iodide, thetitle compound is prepared.

EXAMPLE 987-Fluoro-1-methylamino-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Step 1: 4-Chloro-5-fluoro-alpha-bromo-2-picoline

4-Chloro-5-fluoro-2-picoline (2.9 g, 20 mmol), the product of Example66, was dissolved in 50 mL of 1,2-dichloroethane in a dry flask. Theresultant solution was heated, with stirring, to 75° C. and 4.09 (23mmol) of N-bromosuccinimide was added, followed by 100 mG (0.7 mmol) of2,2-azobisisobutyronitrile (AIBN), a free radical initiator. After thereaction mixture was stirred at 75° C. for 24 hours, it was diluted with450 mL of methylene chloride and washed with 3×400 mL of water. Theorganic layer was separated and dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue was driedin vacuo to give 3.5 g (69% yield) of the title compound as an amberoil; ¹ H NMR (CDCl₃) d 4.50 (s, 2H), 7.54 (d, 1H), 8.44 (s, 1H).

Step 2: 4-Chloro-5-fluoro-2-(N-methylaminomethyl)-pyridine

4-Chloro-5-fluoro-alpha-bromo-2-picoline (1.37 g, 6.1 mmol), from Step 1was dissolved in 15 mL of methanol in a pressure tube. Methylamine (3 mLof 40% aqueous solution) was added to the tube and the tube was sealed.The reaction mixture was stirred at ambient temperature for 26 hours andthen the solvent was removed under reduced pressure. To the residue wasadded 50 mL of 10% aqueous sodium carbonate solution and the resultantaqueous mixture was extracted with 3×50 mL of methylene chloride. Theorganic combined extract was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressur. The residue was driedin vacuo to give 754 mg g (70% yield) of the title compound; MS DCI-NH₃M/Z: 175 (M+H)⁺ base; ¹ H NMR (CDCl₃) d 2.50 (s, 3H), 3.90 (s, 2H), 7.47(d, 1H), 8.42 (s, 1H).

Step 3:N-(4chloro-5-fluoro-2-pyridyl)methyl-N-methyl-N-(2,2-dimethylethyl)-formamidine

4-Chloro-5-fluoro-2-(N-methylaminomethyl)-pyridine (650 mg, 3.72 mmol),from Step 2 was dissolved in 15 mL of toluene. To the resultant solutionwas added 2.3 mL (15 mmol) ofN,N-dimethyl-N-(2,2-dimethylethyl)-formamide, followed by 40 mg (0.3mmol) of ammonium sulfate. The reaction mixture was heated at refluxtemperature, with stirring, for 28 hours and then allowed to cool toambient temperature. The solvent was removed under reduced pressure andthe residue dried in v acuo to give 560 mg (59% yield) of the titlecompound; MS DCI-NH₃ M/Z: 175 (M+H)⁺ 73%, 203 ((M+H)-Cl-F)⁺ base; ¹ HNMR (CDCl₃) d 1.17 (s, 3H), 1.19 (s, 9H), 2.83 (d, 2H), 4.47 (s, 1H),7.43 (d, 1H, J=3 Hz), 8.40 (dd, 1H), J=3 Hz, 1.5 Hz).

Step 4: Diethyl 2-ethoxy-3-(5-fluoropyridin-2-yl)-3-[N-methyl-N-(2",2"-dimethylethyl)methylamino]-propane-1,1-dicarboxylate

Lithium diisopropylamide (LDA: 16 mL of a 1.5M solution in hexane) isadded to 8 mL of dry THF, under a nitrogen atmosphere, and the resultantsolution is cooled to -70° C. in a isopropyl alcohol/dry ice bath. Tothe cooled solution of LDA, is added dropwise, over a 30 minute period,a solution of 3.41 g (19.6 mmol) ofN-(4-chloro-5-fluoro-2-pyridyl)methyl-N-methyl-N-(2,2-dimethylethyl)-formamidine,from Step 3, in 25 mL of dry THF. After stirring the solution for 0.5hours at -70° C., a solution of 4.04 mL (19.6 mmol) ofethoxymethylenemalonate in 18 mL of dry THF is added dropwise over a 30minute period. The reaction solution turns from dark red to orange.After stirring for 0.5 hours at -70° C., the reaction solution isallowed to warm to -20° C. and is stirred at -20° C. for 1 hour. Thereaction is quenched at -20° C. by the addition of 1.3 mL of glacialacetic acid and the cooling bath is removed. After 20 minutes thereaction solution is poured into 5% aqueous sodium bicarbonate solution.The aqueous mixture is extracted with methylene chloride and the organicextract is dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue is purified bychromatography on a silica gel column to afford the title compound.

Step 5: Diethyl2-ethoxy-3-(5-fluoropyridin-2-yl)-3-methylamino-propane-1,1-dicarboxylate

A solution of 2 mmol (0.8 g) of diethyl2-ethoxy-3-(5-fluoropyridin-2-yl)-3-[N-methyl-N-(2",2"-dimethylethyl)methylamino]-propane-1,1-dicarboxylate,from Step 4, 16 mmol of hydrazinc and 6 mml of glacial acetic acid in 20mL of 95% ethyl alcohol is heated at 50° C. under nitrogen forapproximately 15 hours. Upon cooling, the solvent is removed in vacuoand the residue extracted with diethyl ether. The ether solution iswashed with saturated aqueous sodium bicarbonate solution, dried overanhydrous sodium sulfate, and concentrated in vacuo to afford the titlecompound.

Step 6: Ethyl8-chloro-7-fluoro-1-methylamino-4H-quinolizin-4-one-3-carboxylate

80 mL of Dowtherm A® in a 3-neck flask equipped with a thermometer, anaddition funnel and an air-cooled condenser is heated to 235° C., undernitrogen, using a heating mantel. A solution of 3.9 g (12.4 mmol) ofdiethyl2-ethoxy-3-(5-fluoropyridin-2-yl)-3-methylamino-propane-1,1-dicarboxylate,from Step 5, in 45 mL of Dowtherm A® is added, dropwise over a 1.5 hoursperiod, through the addition funnel to the heated stirring Dowtherm A®.After the addition is complete, the resultant solution is heated at˜200° C. for 1 hour and then is cooled to ambient temperature. Thesolution is then poured into 500 mL of hexane and a precipitate forms.The precipitate is collected by filtration, washed with 5×100 mL ofhexane and dried to afford the title compound.

Step 7: Ethyl7-fluoro-1-methylamino-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-quinolizin-4-one 3-carboxylate

Ethyl 8-chloro-7-fluoro-1-methylamino-4H-quinolizin-4-one-3-carboxylate(899 mg, 3.0 mmol), the product of Step 6, is suspended in 12 mL of drypyridine under a nitrogen atmosphere. To the resultant solution is added6.0 mL (6.0 mmol) of N-methylpiperazine and the reaction mixture isheated at 70° C. for 8 hours. The reaction mixture is then concentratedin vacuo in order to remove all of the pyridine. The dry residue isdissolved in 125 mL of methylene chloride and the methylene chloridesolution is washed with 125 mL of brine. The aqueous layer is extractedwith 125 mL of methylene chloride and the combined methylene chloridesolutions are dried over anhydrous sodium surfate, filtered andconcentrated and dried in vacuo to afford the title compound.

Step 8: 8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylic acidhydrochloride

A mixture of 1 g (2.75 mmol)of ethyl7-fluoro-1-methylamino-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylate,from Step 7, in 12 mL of THF and 16.5 mL of a 0.5N aqueous solution ofsodium hydroxide is heated, with stirring, at 75° C. for 8 hours. TheTHF is removed from the reaction mixture by distillation during thereaction. The concentrated reaction mixture is cooled to ambienttemperature and adjusted to pH 2.0 with 10.5 mL of 1N aqueoushydrochloric acid solution. The aqueous solution is concentrated invacuo to remove ˜80% of the water and the concentrate is diluted with 50mL of 95% ethyl alcohol. The solid is collected by filtration, washedwith 2×5 mL of ethyl alcohol and dried in vacuo to afford the desiredproduct.

EXAMPLES 99-116

By following the procedures described in Example 98 and replacingN-methylpiperazine in Step 7 with the appropriate amine as shown,Examples 99-116 are prepared as disclosed in Table 3 wherein thecompounds have the general formula ##STR54##

                                      TABLE 3                                     __________________________________________________________________________    Example No.                                                                          R.sup.2    Example No.                                                                          R.sup.2                                              __________________________________________________________________________     99                                                                                             108                                                                                   ##STR55##                                           100                                                                                   ##STR56## 109                                                                                   ##STR57##                                           101                                                                                   ##STR58## 110                                                                                   ##STR59##                                           102                                                                                   ##STR60## 111                                                                                   ##STR61##                                           103                                                                                   ##STR62## 112                                                                                   ##STR63##                                           104                                                                                   ##STR64## 113                                                                                   ##STR65##                                           105                                                                                   ##STR66## 114                                                                                   ##STR67##                                           106                                                                                   ##STR68## 115                                                                                   ##STR69##                                           107                                                                                   ##STR70## 116                                                                                   ##STR71##                                           __________________________________________________________________________     *The amines are protected and deprotected as described in Example 58     

EXAMPLE 1177,9-Difluoro-1-methylamino-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

By following the procedures described in Example 98 and replacing4-chloro-5-fluoro-2-picoline (the product of Example 66) with4-chloro-3,5-difluoro-2-picoline (the product of Example 69), the titlecompound is prepared.

EXAMPLES 118-135

By following the procedures described in Example 98, replacing4-chloro-5-fluoro-2-picoline (the product of Example 66) with4-chloro-3,5-difluoro-2-picoline (the product of Example 69) andreplacing N-methylpiperazine with the appropriate amine as shown,Examples 118-135 are prepared as disclosed in Table 4 wherein thecompounds have the general formula ##STR72##

                                      TABLE 4                                     __________________________________________________________________________    Example No.                                                                          R.sup.2    Example No.                                                                          R.sup.2                                              __________________________________________________________________________    118                                                                                             127                                                                                   ##STR73##                                           119                                                                                   ##STR74## 128                                                                                   ##STR75##                                           120                                                                                   ##STR76## 128                                                                                   ##STR77##                                           121                                                                                   ##STR78## 130                                                                                   ##STR79##                                           122                                                                                   ##STR80## 131                                                                                   ##STR81##                                           123                                                                                   ##STR82## 132                                                                                   ##STR83##                                           124                                                                                   ##STR84## 133                                                                                   ##STR85##                                           125                                                                                   ##STR86## 134                                                                                   ##STR87##                                           126                                                                                   ##STR88## 135                                                                                   ##STR89##                                           __________________________________________________________________________     *The amines are protected and deprotected as described in Example 58     

EXAMPLE 1361-Ethyl-8-(4-methylpiperazin-1-yl)-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Step 1: 3,4,5,6-Tertrafluoro-2-picoline

2,3,4,5,6-Pentafluoropyridine (commercially available from AldrichChemical Co.) is oxidized to the corresponding N-oxide following theprocedures described in Step 6 of Example 66. The2,3,4,5,6-pentafluoropyridine N-oxide is treated at ambient temperaturewith one equivalent of methylmagnesium iodide in diethyl ether asdescribed by F. Binns and H. Suschitsky in Chemical Communications,750-751 (1970) and J Chem Soc (C), 1223-1231 (1771). The reactionmixture is treated with aqueous ammonium chloride and extracted withdiethyl ether. The ether solution is dried over anhydrous magnesiumsulfate, filtered and concentated under reduced pressure and the crudeproduct is chromatographed on silica gel to afford2-methyl-3,4,5,6-tetrafluoropyridine N-oxide(3,4,5,6-tetrafluoro-2-picoline). The N-oxide is then reduced to affordthe title compound by the procedures described in Step 8 of Example 66.

Step 2: 2-Propyl-3,4,5,6-tetrafluoropyridine

A 1.5M solution of LDA in hexane (100 mL, 150 mmol) is cooled to -60° C.in an isopropyl alcohol/dry ice bath. To the stirred LDA solution, undernitrogen, is added, dropwise over a 0.5 hours period, a solution of22.617 g (137 mmol) of 3,4,5,6-tetrafluoro-2-picoline, the product ofStep 1, in 80 mL of dry THF. The reaction mixture is stirred for 0.5hours at -60° C. and then a solution of 10.95 mL (137 mmol) of ethyliodide in 30 mL of dry THF is added, dropwise over a 20 minute period.After the reaction mixture is stirred at -60° C. for 0.5 hours, thecooling bath is allowed to slowly (1.5 hours) warm to -30° C. Thereaction mixture is poured into cold brine and the aqueous mixture isextracted with methylene chloride. The organic extract is dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue is distilled to afford the title compound.

Step 3: Diethyl2-ethoxy-3-[3,4,5,6-tetrafluoro-2-pyridyl]-pentane-1,1-dicarboxylate

A solution of 12.6 mL (89.9 mmol) of diisopropylamine in 20 mL ofanhydrous tetrahydrofuran (THF) is prepared under a nitrogen atmosphereand cooled in an ice/water bath. To this solution is added, dropwiseover a 30 minute period, 36 mL of a 2.5M solution of n-butyllithium (90mmol) in hexane. The solution is stirred for 30 minutes at 0° C. andthen cooled to -60° C. To the amine solution at -60° C., is added,dropwise over a 30 minute period, a solution of 15.82 g (81.9 mmol) of2-propyl-3,4,5,6-tetrafluoropyridine, from Step 2, in 100 mL ofanhydrous THF. The resultant solution is stirred at -60° C. for 0.5hours and then 16.55 mL (81.9 mmol) of ethyl2-carboethoxy-3-ethoxy-2-propenecarboxylate is added, dropwise over a 30minute period. Stirring is continued at -60° C. for 0.5 hours and at-20° C. for 1.5 hours. The reaction mixture is poured into cold brineand the aqueous mixture is extracted with methylene chloride. Thecombined organic extract is dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to afford 35.48 g of the titlecompound. The product is carried on to the next step withoutpurification.

Step 4: Ethyl1-ethyl-6,7,8,9-tetrafluoro-4-H-quinolizin-4-one-3-carboxylate

A solution of 40.61 g (99.2 mmol) of diethyl2-ethoxy-3-[4-chloro-2-pyridyl]-pentane-1,1-dicarboxylate, from Step 3,in 1L of xylene is heated at 150° C., with stirring, for 24 hours andthen concentrated in vacuo. The residue is washed with a mixture ofhexane and cyclohexane to afford the title compound.

Step 5: Ethyl1-ethyl-8-(4-methylpiperazin-1-yl)-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylate

Ethyl8-chloro-1-ethyl-6,7,8,9-tetrafluoro-4H-quinolizin-4-one-3-carboxylate(317 mg, 1.0 mmol), from Step 4, is dissolved in 5 mL of dry pyridineunder a nitrogen atmosphere. To the resultant solution is added 2 mL(2.0 mmol) of N-methylpiperazine and the stirred reaction mixture isheated at 85° C. for 2.5 hours. The reaction mixture is allowed to coolto ambient temperature and then concentrated in vacuo in order to removeall of the pyridine. The residue is dissolved in 50 mL of methylenechloride and the methylene chloride solution is washed with 50 mL of 5%aqueous sodium bicarbonate solution. The aqueous layer is extracted with3×50 mL of methylene chloride and the combined methylene chloridesolutions are dried over anhydrous sodium sulfate, filtered andconcentrated and dried in vacuo to afford the title compound.

Step 6:1-Ethyl-8-(4-methylpiperazin-1-yl)-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

To a solution of 199 mg (0.5 mmol) of ethyl1-ethyl-8-(4-methylpiperazin-1-yl)-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylate,from Step 5, in 4 mL of THF is added 4.0 mL of a 1.0N aqueous sodiumhydroxide solution and the reaction mixture is heated, with stirring, at75° C. for 4.5 hours. The reaction mixture is cooled to ambienttemperature and adjusted to pH 2 with 5 mL of 1N aqueous hydrochloricacid solution. The aqueous solution is concentrated in vacuo to ˜5 mLand the solid is collected by filtration and dried in vacuo to affordthe title compound.

EXAMPLE 1378-(3-Amino-1-1-pyrrolidinyl)-1-ethyl-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

Step 1: Ethyl8-(3-(N-t-butoxycarbonyl)amino-1-pyrrolidinyl)-1-ethyl-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylate

Ethyl 6,7,8,9-tetrafluoro-1-ethyl-4H-quinolizin-4-one-3-carboxylate(1.26 g, 3.97 mmol), from Step 3 of Example 136, is dissolved in 20 mLof dry pyridine under a nitrogen atmosphere. To the resultant solutionis added a solution of 1.85 g (9.92 mmol) of3-(N-tbutoxycarbonylamino)pyrrolidine in 5 mL of dry pyridine and thereaction mixture is heated at 70° C. for 4.5 hours. The reaction mixtureis then concentrated in vacuo in order to remove all of the pyridine.The dry residue (3.124 g) is purified by chromatography on silica gel toafford the title compound.

Step 2: 8-(3-Amino-1-pyrrolidinyl)-1-ethyl-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylicacid hydrochloride

A solution of 1.11 g (2.2 mmol) of ethyl8-(3-(N-t-butoxycarbonyl)amino-1-pyrrolidinyl)-1-ethyl-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylate,from Step 1, in 20 mL of trifluoroacetic acid (TFA) is stirred for 2hours at ambient temperature. The TFA is evaporated in vacuo and theresidue is dissolved in 200 mL of methanol. To the resultant solution isadded 4.5 g of strongly basic ion exchange resin and the mixture isstirred at ambient temperature for 1 hour. The mixture is filtered andthe filtrate is concentrated under reduced pressure to afford crudeethyl8-(3-amino-1-pyrrolidinyl)-1-ethyl-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylateas a residue. The residue is dissolved in 5 mL of THF and 11 mL of a 1Maqueous solution of sodium hydroxide is added. The reaction mixture isheated at 60° C. for 1 hour and then the reaction temperature isincreased to 85° C. in order to evaporate the THF. The concentratedreaction solution is diluted with 20 mL of water and the pH of theresultant solution is adjusted to 0 with concentrated hydrochloric acid.The aqueous solution is concentrated in vacuo. The residue iscrystallized from ethyl alcohol:isopropyl alcohol:water (4:4:1 v/v/v)and recrystallized from ethyl alcohol/water to afford the titlecompound.

EXAMPLE 1381-Ethyl-8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylicacid

3-Amino-1-benzylpyrrolidine (I. Sumio and T. Matsuo, Japanese Kokai JP5328161, published Mar. 16, 1978) is coupled to N-t-butoxycarbonylnorvaline (Boc-nVal) using conventional N-hydroxysuccinimide couplingprocedures. The 1-benzyl group is removed by hydrogenolysis in methanolusing palladium on carbon catalyst. The3-(N-Boc-norvalyl)aminopyrrolidine is then reacted with ethyl6,7,8,9-tetrafluoro-1-ethyl-4H-quinolizin4-one-3-carboxylate, asdescribed in Step 1 of Example 137, replacing3-(N-t-butoxycarbonylamino)pyrrolidine with3-(N-Boc-norvalyl)aminopyrrolidine, to give1-ethyl-8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylicacid with the nitrogen of the amino acid protected with a Boc group. TheBoc protecting group is removed by standard hydrolysis usingtrifluoroacetic acid and dilute aqueous hydrochloric acid.

Using the procedure outlined in Example 138, or any of the otherconventional condensation methods listed above, other amino acidderivatives of the compounds of this invention having an amino group canbe prepared. Examples of amino acids which can be coupled, either aloneor in combination with one and other, include naturally occurring aminoacids such as glycine, alanine, leucine, isoleucine, methionine,phenylalanine, valine, and the like, as well as synthetic amino acidssuch as cyclohexylalanine, cyclohexylglycine, aminopentanoic acid, andthe like.

EXAMPLES 139-155

By following the procedures described in Example 136 or Example 137 andreplacing N-methylpiperazine or 3-(N-t-butoxycarbonylamino)pyrrolidinewith the appropriate amine as shown, Examples 139-155 are prepared asdisclosed in Table 5 in which the compounds have the general formula##STR90##

                                      TABLE 5                                     __________________________________________________________________________    Example No.                                                                          R.sup.2    Example No.                                                                          R.sup.2                                              __________________________________________________________________________    139                                                                                             148                                                                                   ##STR91##                                           140                                                                                   ##STR92## 149                                                                                   ##STR93##                                           141                                                                                   ##STR94## 150                                                                                   ##STR95##                                           142                                                                                   ##STR96## 151                                                                                   ##STR97##                                           143                                                                                   ##STR98## 152                                                                                   ##STR99##                                           144                                                                                   ##STR100##                                                                              153                                                                                   ##STR101##                                          145                                                                                   ##STR102##                                                                              154                                                                                   ##STR103##                                          146                                                                                   ##STR104##                                                                              155                                                                                   ##STR105##                                          147                                                                                   ##STR106##                                                            __________________________________________________________________________     *The amines are protected and deprotected as described in Example 58     

EXAMPLE 15611,12-Dihydro-7-fluoro-12-methyl-8-(4-methyl-1-piperazinyl)-4H-pyrano[i,j]quin-olizin-4-one-3-carboxylicacid

Step 1:4-Chloro-3,5-difluoro-2-(1-(2-tetrahydropyranyl)oxy-2-propy)pyridine

A solution of 12.8 g (150 mmol) of 2-chloro-1-propanol is dissolved in200 mL of acetone. To the resultant solution are added 40 g of anhydrousferric chloride and 30 g (200 mmol) of sodium iodide. The reactionmixture is stirred at room temperature for 24 hours and then filtered toremove sodium chloride. The solvent is evaporated to afford thecorresponding 2-iodo-1-propanol. The iodo alcohol is dissolved in 200 mLof methylene chloride and is treated with 20.5 mL (225 mmol) of3,4-dihydro-2H-pyran and 50 mg of p-toluenesulfonic acid. The reactionmixture is stirtred at room temperature for several hours and thenpoured into 200 mL of 5% aqueous sodium bicarbonate solution. Theaqueous mixture is extracted with methylene chloride. The methylenechloride solution is dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford the THP-protected2-iodo-1-propanol.

A solution of 4-chloro-3,5-difluoro-2-methylpyridine (16.5 g, 100 mmol)in 150 mL of dry THF under a positive nitrogen atmosphere is treatedwith 73 mL of 1.5M lithium diisopropylamine (LDA) at -78° C. Afterstirring at -78° C. for 30 minutes, a solution of 27.0 g (100 mmol) ofthe THP-protected 1-iodo-2-propanol in 150 mL of THF is added dropwisewith stirring. The reaction mixture is stirred at -78° C. for severalhours and then is slowly warmed to -20° C. The reaction is quenched bypouring the reaction mixture into 400 mL of saturated aqueous ammoniumchloride solution. The aqueous layer is separated and extracted withmethylene chloride. The combined organic layers are dried over anhydroussodium surfate, filtered and concentrated under in vacuo to afford thetitle compound.

Step 2: 4-Chloro-3,5-difluoro-2-(1-hydroxy-2-propyl)pyridine

The product of Step 1 is dissolved in 200 mL of 2:1 THF:water and tothis solution is added 6 mL of acetic acid. The reaction mixture isheated at 45° C. for approximately 5 hours. The THF is removed underreduced pressure and the aqueous reaction mixture is adjusted to a pH inthe range of 8 to 9 with 10% sodium carbonate and is then extracted withmethylene chloride. The organic layer is dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to afford the titlecompound.

Step 3: 8-Chloro-3,4-dihydro-7-fluoro-3-methyl-2H-pyrano[3,2-b]pyridine

The product of Step 2 (15.5 g, 75 mmol) is dissolved in 100 mL of dryTHF in an oven-dried system under positive nitrogen atmosphere. Thereaction mixture is cooled in ice and 3.2 g (80 mmol) of 60% sodiumhydride is added. The reaction mixture is warmed to room temperature andthen heated at reflux temperature overnight with stirring. The reactionmixture is cooled to room temperature and poured into brine. The aqueousmixture is extracted with ethyl acetate. The organic layer is dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo toafford the title compound.

Step 4: Diethyl2-(8-chloro-3,4-dihydro-7-fluoro-3-methyl-2H-pyrano[3,2-b]pyridin-4-yl)-2-ethoxy1,1-ethanedicarboxylate

Following the procedure described in Step 2 of Example 62, the productof Step 3 is treated with ethyl2-carboethoxy-3-ethoxy-2-propenecarboxylate and LDA to afford the titlecompound.

Step 5: Ethyl8-chloro-11,12-dihydro-7-fluoro-12-methyl-4H-pyrano[i,j]quin-olizin-4-one-3-carboxylate

Following the procedures described in Step 3 of Example 62, the productof Step 4 is heated in refluxing Dowtherm A® to afford the desiredcyclized product.

Step 6: Ethyl11,12-dihydro-7-fluoro-12-methyl-8-(4-methyl-1-piperazinyl)-4H-pyrano[i,j]quin-olizin-4-one-3-carboxylate

Following the procedures described in Step 1 of Example 65, the productof Step 5 is reacted with N-methylpiperazine to afford the titlecompound.

Step 7:11,12-Dihydro-7-fluoro-12-methyl-8-(4-methyl-1-piperazinyl)-4H-pyrano[i,j]quin-olizin-4-one-3-carboxylic acid

Following the procedures described in Step 2 of Example 65, the tilecompound is prepared.

EXAMPLE 1572-(3-Aminopyrrolidin-1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid hydrochloride salt

Step 1: 2-Cyclopropyl-2-ethoxycarbonylacetamidine hydrochloride

Into a stirred solution of 38.72 g (0.253 mol) of ethyl2-cyano-2-cyclopropylacetate (preparation described by R. W. J. Carneyand J. Wojtkunski, Org. Prep. Proced. Int., 5, 25 (1973)) in 17.7 mL(0.303 mol) of anhydrous ethanol under a dry N₂ atmosphere wasintroduced 10.0 g (0.274 mol) of gaseous hydrogen chloride with icecooling. The mixture was allowed to warm to room temperature and standfor 72 hours. The reaction was diluted with 100 mL of anhydrous ethanol,70 mL of ammonia in ethanol (4.17M) was added slowly at room temperatureand the reaction was stirred for 3 hours. The reaction mixture wasfiltered to remove the ammonium chloride, and the solvent was removed toafford the title compound as a viscous off-white oil, which was takendirectly to the next step.

Step 2: 2-Cyclopropyl-2-(5-fluoro-4-hydroxypyrimidin-2-yl)acetic acidmethyl ester and2-cyclopropyl-2-(5-fluoro-4-hydroxypyrimidin-2-yl)acetic acid ethylester

A mixture of 0.253 mol of the compound from Step 1, 0.254 mol of thesodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (prepared asdescribed by E. Elkik and M. Imbeaux-Oudotte, Bull. Soc. Chim. Fr., 5-6pt2, 1165(1975))and 37.0 ml (0.265 mol) of triethylamine in 250 mL ofanhydrous methanol was heated at reflux under a dry N₂ atmosphere for 17hours. The solvent was removed, 200 mL of water added and the residueacidified to pH 5 with acetic acid. This mixture was then extracted withmethylene chloride. The extract was washed with water, dried overanhydrous magnesium sulfate, and the solvent was removed by evaporationunder vacuum to give a dark brown oil. The product was purified bycolumn chromatography on silica gel eluting with 1:1 ethylacetate:hexane to afford 22.8 g of the methyl ester title compound as apale yellow viscous oil and 6.45 g of the ethyl ester title compound asa pale yellow viscous oil. Methyl ester: MS M/Z: 227 (M+H). NMR (CDCl₃):d 0.43 (1H, m), 0.52 (1H, m), 0.65 (1H, m), 0.77 (1H, m), 1.42 (1H, m),2.97 (1H, d, J=10 Hz), 3.80 (3H, s), 7.88 (1H, d, J=3 Hz), 11.8 (1H, b).IR: (neat) 1740, 1690, 1615 cm⁻¹. Analysis calculated for C₁₀ H₁₁ FN₂O₃. 1/4 H₂ O: C, 52.06; H, 5.02; N, 12.14. Found: C, 52.45; H, 4,94; N,11.76.

Ethyl ester: MS M/Z: 258 (M+NH₄). NMR (CDCl₃): d 0.47 (1H, m), 0.54 (1H,m), 0.66 (1H, m), 0.74 (1H, m), 1.31 (3H, t, J=7 Hz), 1.34 (1H, m), 2.96(1H, d, J=10 Hz), 4.27 (2H, m), 7.83 (1H, d, J=3 Hz), 11.0 (1H, b): IR:(neat) 1735, 1682, 1605 cm⁻¹. Analysis calculated for C₁₁ H₁₃ FN₂ O₃.0.3H₂ O: C, 53.78 H, 5.58; N, 11.40. Found: C54.05; H 5.59; N, 11.11.

Step 3: 2-Cyclopropyl-2-(5-fluoro-4-hydroxypyrimidin-2-yl)acetaldehyde

To a solution of 4.960 g (21.9 mmol) of the methyl ester compound fromStep 2 in 40 mL of toluene stirred at -70° C. under a dry N₂ atmospherewas added 46.0 mL of 1N diisobutylaluminum hydride in toluene (46 mmol).The reaction was stirred for 40 min and then quenched by the addition of5 mL of acetic acid. The mixture was allowed to warm to roomtemperature, and the reaction was extracted with ethyl acetate. Theextract was washed with water (3×), dried over anhydrous magnesiumsulfate and concentrated under vacuum to afford 2.230 g of the titlecompound as a white solid. This compound was used directly in the nextstep.

MS M/Z: 214 (M+NH₄). NMR:(CDCl₃) d 0.48 (m, 2H), 0.91 (m, 2H), 1.35 (m,1H0, 7.40 (d, 1H, J=10 Hz), 7.75 (d, 1H, J=4 Hz), 9.61 (br s, 1H), 13.64(d, 1H, J=10 Hz). IR (KBr) 1695, 1660, 1635 cm⁻¹.

Step 4:9-Cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo-pyridol[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

A 2.230 g (11.37 mmol) sample of the compound from Step 3 was dissolvedin 100 mL of anhydrous ethanol. To this was added 3.5 mL (14.00 mmol) ofdibenzyl malonate, 2.5 mL of piperidine and 0.25 mL of acetic acid. Thisreaction mixture under a dry N₂ atmosphere was heated under refluxconditions for 3 hours and stirred at room temperature overnight. Thesolvent was removed by evaporation, the residue was dissolved inmethylene chloride which was washed with water and dried over anhydrousmagnesium sulfate. The solvent was removed by evaporation under vacuumto give a yellow oil, which was purified by column chromatography onsilica gel, eluting with 1:5:100 acetic acid:methanol:methylenechloride. Removal of the solvent afforded 1.800 g of the title compoundas a pale yellow solid, mp 225.5°-226.5° C. MS M/Z 355 (M+H).NMR:(CDCl₃) d 0.64 (m, 2H), 1.08 (m, 2H), 1.62 (m, 1H), 5.37 (s, 2H),7.35-7.48 (m, 5H), 8.28 (s, 1H), 9.00 (d, 1H, J=6 Hz). IR (KBr) 1720,1700, 1690 cm⁻¹. Analysis calculated for C₁₉ H₁₅ FN₂ O₄. 1/4 H₂ O: C,63.60; H, 4.35; N, 7.81. Found: C, 63.54; H, 4.08; N, 7.78.

Step 5:2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

A mixture of 0.200 g (0.564 mmol) of the compound from Step 4, 0.50 mLof DMF, 0.60 mL of phosphorous oxychloride and 10 mL of methylenechloride was stirred under a dry N₂ atmosphere at room temperature for 4hours. Ice was added to react with the excess phosphorous oxychloride.The mixture was extracted with methylene chloride, which was washed withwater, then the solvent was dried over anhydrous magnesium sulfate andthe solvent was removed by evaporation under vacuum to yield the titlecompound as an orange residue. This compound was taken directly to thenext step.

Step 6:2-(3-(N-t-butoxycarbonyl)aminopyrrolidin-1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

The 0.564 mmol sample of the compound from the previous step wasdissolved in 5 mL of dry methylene chloride and cooled to 0° C. To thissolution was added 0.45 g of 3-(N-t-butoxycarbonyl)aminopyrrolidine, andthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed by evaporation under vacuum, and the product waspurified by column chromatography on silica gel, eluting with 10%methanol in methylene chloride to afford 0.295 g of the title compoundas a yellow solid, mp 159°-160° C. MS M/Z 523 (M+H). NMR:(CDCl₃) d 0.60(m, 2H), 0.87 (m, 2H), 1.46 (s, 9H), 1.90-2.40 (m, 2H), 3.70-4.45 (m,5H), 4.94 (br s, 1H), 5.37 (s, 2H), 7.29 (m, 1H), 7.37 (m, 2H), 7.50 (m,2H), 7.99 (br s, 1H), 9.10 (d 1H, J=10 Hz). IR (KBr) 1715, 1685, 1660cm⁻¹. Analysis calculated for C₂₈ H₃₁ FN₄ O₅. 1/2 H₂ O: C, 63.44; H,6.08; N, 10.57. Found: C, 63.39; H, 6.13; N, 10.83.

Step 7:2-(3-(N-t-butoxycarbonyl)aminopyrrolidin-1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid

To a 0.135 g (0.259 mmol) sample of the benzyl ester from Step 6 in 20mL of methanol and 2 mL of THF was added 2.0 mL of 98% formic acid and0.05 g of 10% Pd/C. This mixture was stirred under a dry N₂ atmosphereat room temperature for 37 min. The catalyst was removed by filtration,and the solvent was removed under vacuum. The crude product was purifiedby column chromatography on silica gel, eluting with 1:5:100 aceticacid:methanol:methylene chloride to afford the title compound as ayellow solid after removal of the solvent. This product was takendirectly to the next step.

Step 8:2-(3-Aminopyrrolidin-1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid hydrochloride salt

The sample of the compound from the previous step was reacted with 10 mLof 4N HCl in dioxane under a dry N₂ atmosphere at room temperature 3hours. The solvent was removed, the yellow solid was dissolved indistilled water. The yellow solution was filtered and freeze-dried toafford 0.0681 g of the title compound as a yellow solid, mp 234° C.,(dec.). MS M/Z 333 (M--Cl). NMR: (CDCl₃) d 0.64 (m, 2H), 0.96 (m, 2H),2.20-2.65 (m, 3H), 3.58-4.35 (m, 5H), 7.80 (d, 1H, J=10 Hz), 9.05 (br s,1H), IR (KBr) 1665, 1620 cm⁻¹.

EXAMPLE 1582-(3-Aminopyrrolidin-1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

Step 1:9-Cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid t-butyl ester

A 0.247 g (1.262 mmol) sample of2-cyclopropyl-2-(5-fluoro-4-hydroxypyrimidin-2-yl)acetaldehyde, fromExample 157 Step 3 above, was dissolved in 20 mL of ethanol, and 0.290mL of ethyl t-butyl malonate, 0.5 mL of piperidine and 0.05 mL of aceticacid were added. The reaction was heated under a dry N₂ atmosphere atreflux for 25 hours, the solvents were removed by evaporation and theproduct was purified by column chromatography on silica gel, elutingwith 1:10:100 acetic acid:methanol:methylene chloride. Removal of thesolvent afforded 0.287 g of the title compound as a pale yellow solid,mp >265° C. MS M/Z 321 (M+H). NMR: (CDCl₃ +CD₃ OD) d 0.61 (m, 2H), 1.06(m, 2H), 1.58 (s, 9H), 172 (m, 1H), 8.07 (s, 1H), 8.93 (d, 1H, J=6 Hz).IR (KBr)1720, 1525 cm-1.

Step 2:2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid t-butyl ester

A mixture of 0.100 g (0.312 mmol) of the compound from Step 1, 0.29 mLof DMF, 0.33 mL of phosphorous oxychloride and 10 mL of methylenechloride was stirred under a dry N₂ atmosphere at room temperature for 1hour. After workup as described in Example 157 Step 5. the titlecompound was obtained as a orange solution in methylene chloride. Thiscompound was taken directly to the next step.

Step 3:2-(3-(N-t-butoxycarbonyl)aminopyrrolidin-1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid t-butyl ester

To the 0.312 mmol sample in methylene chloride from the previous step atroom temperature was added several small portions of3-(N-t-butoxycarbonyl)aminopyrrolidine until the color of the reactionturned from orange to light yellow. The solution was concentrated toleave a yellow residue. The product was purified by columnchromatography on silica gel, eluting with 10:100 methanol: methylenechloride to afford 0.132 g of the title compound as a yellow solid afterremoval of the solvent. This compound was taken directly to the nextstep.

Step 4:2-(3-aminopyrrolidin-1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

The boc-protected t-butyl ester from Step 4 was hydrolyzed by reactingthe 0.132 g sample with 1 mL of 4N HCl in dioxane under a dry N₂atmosphere. The solvent was removed, the yellow solid was dissolved inwater and the solution adjusted to pH 7-8, and extracted with methylenechloride. The reaction was incomplete at this point, so the solid wasredissolved in 5 mL of trifluoroacetic acid and the reaction stirred atroom temperature overnight. The solvent was removed by evaporation. Theresidue was redissolved and extracted as above, then the product waspurified by column chromatography on silica gel, eluting with 2:5:20:100water:acetic acid:methanol:methylene chloride to afford 0.0515 g of thetitle compound as a yellow solid.

EXAMPLE 1599-(2,4-Difluorophenyl)-3-fluoro-2-(4methylpiperazin-1-yl)-6H-6-oxopyridol[1,2-a]pyrimidine-7-carboxylicacid

Step 1: 2-(2,4-Difluorophenyl)-acetamine hydrochloride

Into a solution of 49.44 g (0.323 mol) of 2,4-difluorophenylacetonitrile(commercially available) in 20.8 mL (0.354 mol) of ethanol cooled to 0°C. in an ice bath and stirred under a dry N₂ atmosphere was added 14.61g (0.400 mol) of gaseous HCl. After 20 min the reaction mixturesolidified, this was then allowed to warm to room temperature and heldat this temperature for 72 hours. To the mixture was then added 140 mLof ethanol, followed by 150 mL (0.42 mol) of 4.2M ammonia in ethanol.This mixture was stirred for an additional 3 hours at room temperatureand filtered. The solvent was removed from the filtrate by evaporationto afford 65.7 g of the title compound as a white solid, mp 163°-164° C.NMR: (DMSO-d6) d 3.72 (s, 2H), 7.16 (m, 1H), 7.33 (m, 1H), 7.50 (m, 1H),8.95 (broad, 4H). This compound was taken directly to the next step.

Step 2: 2-(2,4-Difluorobenzyl)-5-fluoro-4-hydroxypyrimidine

A mixture of 68.0 g (0.33 mol) of the compound from Step 1, 0.34 mol ofthe sodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (prepared asdescribed by E. Elkik and M. Imbeaux-Oudotte, Bull. Soc. Chim. Fr., 5-6pt 2, 1165 (1975)), 300 mL of anhydrous methanol and 50 mL oftriethylamine was heated at reflux under a dry N₂ atmosphere for 23hours. The solvent was removed by evaporation under vacuum, 200 mL ofwater added and the mixture acidified to pH 3-4 with 10% HCl. Thismixture was then extracted with methylene chloride. The solvent waswashed with water, dried over anhydrous magnesium sulfate, and thesolvent was removed by evaporation under vacuum to give a dark oil whichsolidified upon standing. The sold was washed with ethyl acetate, ethylacetate/hexane and hexane to afford 29.8 g of the title compound as awhite solid, mp 155°-156° C. A second crop of 10.2 g of product wasobtained from the filtrates after chromatography on silica gel, elutingwith 2.5% methanol in methylene chloride. MS M/Z: 258 (M=NH₄), 241(M+H). NMR: (CDCl₃) d 4.02 (s, 2H), 6.88 (m, 2H), 7.33 (m, 1H), 7.89 (d,1H, J=3 Hz). IR (KBr): 1690, 1605 cm⁻¹. Analysis calculated for C₁₁ H₇F₃ N₂ O: C, 55.00; H, 2.94; N, 11.67. Found: C, 54.63; H, 2.98; N,11.50.

Step 3: 4-Chloro-2-(2,4-difluorobenzyl)-5-fluoropyrimidine

A mixture of 1.000 g (4.16 mmol) of the compound from Step 2, 3.40 mL(43.7 mmol) of DMF and 3.90 mL (43.7 mmol) of phosphorous oxychloride in15 mL of methylene chloride was stirred under a dry N₂ atmosphere atambient temperature for 2 hours, then quenched with water and ice. Themixture was then extracted with methylene chloride, which was washedwith water, dried, filtered and concentrated to yield the title compoundas a yellow oil. MS M/Z: 259 (M+H). NMR: (CDCl₃) d 4.27 (s, 2H), 6.83(m, 2H), 7.27 (m, 1H), 8.48 (s, 1H). This compound was taken directly tothe next step.

Step 4:2-(2,4-Difluorobenzyl)-5-fluoro-4-(4-methylpiperazin-1-yl)pyrimidine

To the 4.16 mmol of the compound from Step 3 in 10 mL of methylenechloride was added 3 mL of N-methylpiperidine and the mixture wasstirred under a dry N₂ atmosphere at room temperature for 1 hour. Thesolvent was removed by evaporation, and the product was purified bycolumn chromatography on silica gel eluting with 5% methanol inmethylene chloride. The solvent was removed by evaporation to afford1.229 g of the title compound as a pale yellow oil, MS M/Z: 323 (M+H).NMR: (CDCl₃) d 2.32 (s, 3H), 2.46 (t, 4H, J+7 Hz), 3.75 (t, 4H, J=7 Hz),4.05 (s, 2H), 6.80 (m, 2H), 7.25 (m, 1H), 7.99 (d, 1H, J=7 Hz). Analysiscalculated for C₁₆ H₁₇ F₃ N₄ : C, 59.61; H, 5.32; N, 17.38. Found: C,59.63; H, 5.31; N, 17.31.

Step 5:3-(2,4-Difluorophenyl)-2-ethoxy-3-(5-fluoro-4-(4-methylpiperidin-1-yl)pyrimidin-2-yl)propane-1,1-dicarboxylicacid diethyl ester

Following the procedure of Step 4 Example 1 the compound from Step 4above (0.74 g, 2.3 mmol), 1.0 mL (2.5 mmol) of a 2.5M solution ofn-butyllithium in hexane and 0.35 mL of diisopropylamine was reactedwith 0.46 mL ethyl 2-carboethoxy-3-ethoxy-2-propenecarboxylate, toafford after work-up 1.22 g of the title compound as an oil. Thismaterial was further purified by column chromatography over silica gel,eluting with 5% ethanol in ethyl acetate to give 0.774 g of an oil; MSM/Z: 539 (M+H). NMR: (CDCl₃) d 0.87 (m, 3H), 1.22 (m, 6H), 2.34 (s, 3H),2.50 (m, 4H), 3.52 (m, 2H), 3.81 (m, 4H), 4.16 (m, 5H), 4.82 (m, 1H),4.99 (m, 1H), 6.78 (m, 2H), 7.59 (m, 1H), 8.01 (m, 1H).

Step 6:9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid ethyl ester

To a 1.847 g (3.43 mmol) sample of the compound from Step 5 dissolved in40 mL of anhydrous ethanol was added 1.5 mL of piperidine and 0.05 mL ofacetic acid, and the reaction was heated at reflux conditions under adry N₂ atmosphere for 3 hours. The solvent was removed by evaporation toleave a yellow solid which was purified by column chromatography oversilica gel, eluting with 0.5:10:100 28% aq. NH₄ OH:methanol:methylenechloride to afford after removal of the solvent 1.282 g of the titlecompound as a yellow solid, mp 193°-195° C. MS M/Z: 447 (M+H). NMR:(CDCl₃) d 1.40 (t, 3H, J=7 Hz), 2.33 (s, 3H), 2.50 (m, 4H), 3.89 (m,4H), 4.39 (q, 2H, J=7 Hz), 6.91 (m, 2H), 7.33 (m, 1H), 8.37 (s, 1H),9.16 (d, 1H, J=10 Hz). IR (KBr): 1725, 1685, 1660 cm⁻¹. Analysiscalculated for C₂₂ H₂₁ F₃ N₄ O₃.0.5 H₂ O; C, 58.02; H, 4.87; N, 12.30.Found: C, 58.15; H, 4.70; N, 12.15.

Step 7:9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

A mixture of a 1.166 g (2.61 mmol) sample of the ethyl ester compoundfrom Step 1, 150 mL of dry benzyl alcohol and 0.5 mL of titaniumtetramethoxide was heated under a dry N₂ atmosphere with stirring atreflux conditions for 17 hours. The solvent was removed by distillationat 100° C. under reduced pressure in a kugelrohr apparatus. The productwas purified by column chromatography on silica gel, eluting with0.5:10:100 28% aq. NH₄ OH:methanol:methylene chloride to afford afterremoval of the solvent 0.895 g of the title compound as a yellow solid,mp 207°-208° C. MS M/Z: 509 (M+H). NMR: (CDCl₃) d 2.33 (s, 3H), 2.50 (m,4H), 3.88 (m, 4H), 5.38 (s, 2H), 6.90 (m, 2H), 7.30-7.50 (m, 6H), 8.37(s, 1H), 9.17 (d, 1H, J=10 Hz). IR (KBr): 1730, 1685, 1660 cm⁻¹.

Step 8:9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid

A 0.300 g (0.590 mmol) sample of the benzyl ester from Step 7 wasdissolved in 40 mL of dry methanol and 0.1 g of 10% Palladium on carbonwas added. Four mL of 98% formic acid was added and the mixture stirredunder a dry N₂ atmosphere for 20 min. The catalyst was removed byfiltration through diatomaceous earth, and the solvent was removed undervacuum. The product was purified by column chromatography on silica gel,eluting with 1:10:100 acetic acid:methanol:methylene chloride give ayellow solid. This material was washed with pH 7.5 sodium bicarbonatesolution, followed by water rinse to afford 0.178 g of the titlecompound as a yellow solid, mp 246°-248° C. (dec.). MS M/Z: 419 (M+H).NMR: (CDCl₃ +CD₃ OD) d 2.34 (s, 3H), 2.53 (m, 4H), 3.85-4.00 (m, 4H),6.90 (m, 2H), 7.32 (m, 1H), 8.49 (s, 1H), 9.07 (d, 1H, J=9 Hz). IR(KBr): 1720, 1660 cm⁻¹. Analysis calculated for C₂₀ H₁₇ F₃ N₄ O₃ : C,57.42; H, 4.10; N, 13.39. Found: C, 57.21; H, 4.08; N, 13.21.

EXAMPLE 1602-(3-(N-t-butoxycarbonyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid

Step 1.3-(2,4-Difluorophenyl)-2-ethoxy-3-(5-fluoro-4-hydroxypyrimidin-2-yl)propane-1,1-dicarboxylicacid diethyl ester

A 4.804 g (20.0 mmol) sample of2-(2,4-Difluorobenzyl)-5-fluoro-4-hydroxypyrimidine (prepared asdescribed in Step 2 Example 159 above) was dissolved in 150 mL of dryTHF and cooled to -78° C. with stirring under a dry N₂ atmosphere. Tothis was slowly added 16.40 mL of 2.5N n-butyllithium in hexane, and themixture was stirred for 30 min. Then 4.85 mL (24 mmol) of diethylethoxymethylenemalonate was added and the mixture stirred for anadditional 30 min at -78° C. The reaction mixture was quenched with 10%HCl until the mixture was at pH 3, whereupon it was then extracted withethyl acetate. This was dried over anhydrous magnesium surfate and thesolvent was removed by evaporation under vacuum to afford the titlecompound as a yellow oil. This material was taken directly to the nextstep.

Step 2.9-(2,4-Difluorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid ethyl ester

The compound from Step 1 was dissolved in 80 ml of ethanol, 2 mL ofpiperidine and 0.2 mL of acetic acid was added and the mixture heated atreflux (bath temperature at 90° C.) for 16 hours under a dry N₂atmosphere. The solvent was removed by evaporation, and the residue waswashed with methanol and methylene chloride to give 4.794 g of a paleyellow solid. The washings were concentrated and the residue waspurified by column chromatography on silica gel, eluting with 2:10:100acetic acid:methanol:methylene chloride to afford an additional 2.220 gof the title compound as a pale yellow solid, mp 239°-240° C. MS M/Z:382 (M+NH₄), 365 (M+H). NMR:(DMSO-d₆) d 1.23 (t, 3H, J=7 Hz), 4.14 (q,2H J=7 Hz), 7.08 (m, 1H), 7.21 (m, 1H), 7.40 (m, 1H), 7.83 (s, 1H), 8.74(d, 1 H, J=8 Hz). IR (KBr) 1710, 1675, 1620 cm⁻¹.

Step 3.9-(2,4-Difluorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

To a 7.000 g sample of the ethyl ester compound from Step 2 dissolved in200 mL of benzyl alcohol was added 0.70 mL of titanium tetraethoxide andthe mixture heated with stirring at 100° C. for 2.5 hours under a dry N₂atmosphere. The reaction was diluted with methylene chloride, thenwashed once with 1N HCl and three times with water, and the solvent wasdried over anhydrous magnesium sulfate and removed by evaporation undervacuum to leave a yellow solid. This material was washed with ether anddried under vacuum to afford 6.655 g of the title compound as a yellowsolid, mp 218°-219° C. MS M/Z 427 (M+H). NMR:(DMSO-d₆) d 5.26 (s, 2H),7.15-7.45 (m, 8H), 8.00 (s, 1H), 9.00 (d, 1H, J=7 Hz). IR (KBr) 1710,1675, 1620 cm⁻¹.

Step 4.2-(3-(N-t-butoxycarbonyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridol[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

A 1.200 g (2.815 mmol) sample of the compound from Step 3 was dissolvedin 45 mL of methylene chloride and 2.50 mL of DMF and 2.95 mL of POCl₃were added. The reaction was stirred under a dry N₂ atmosphere at roomtemperature for 2.5 hours, then quenched with ice and water. The mixturewas extracted with methylene chloride, and the solvent was washed withwater until the acidity of the rinse water was above pH 3. The solventwas then dried with magnesium sulfate and an excess of2-(N-t-butoxycarbonylamino)pyrrolidine was added and allowed to react.The solution was then concentrated and the product was purified bycolumn chromatography over silica gel eluting with 0.5:5:100 conc.ammonium hydroxide:methanol:methylene chloride. The solvent was removedto afford 1.579 g of the title compound as a light yellow crystallinesolid, mp 103°-104° C. MS M/Z: 595 (M+H). NMR: (CDCl₃) d 1.45 (s, 9H),1.85-2.30 (m, 2H), 3.42-4.35 (m, 5H), 4.65 (br s, 1H), 5.38 (s, 2H),6.89 (m, 2H), 7.30-7.50 (m, 6H), 8.35 (s, 1H), 9.15 (d, 1H, J=9 Hz),9.16 (d, 1H, J=9 Hz). IR (KBr): 1735, 1710, 1660 cm⁻¹.

Step 5.2-(3-(N-t-butoxycarbonyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid

A 1.769 g sample of the compound from Example 160 Step 4 was dissolvedin 80 mL of dry methanol, and the benzyl ester was removed by reactingwith 4.0 mL of 98% formic acid in the presence of 0.200 g of 10% Pd/Cunder a dry N₂ atmosphere. After filtration and evaporation of thesolvent, the product was purified by column chromatography on silicagel, eluting with 1:10:100 acetic acid:methanol:methylene chloride toafford, after removal of the solvent, 1.125 g of the title compound as ayellow solid, mp 209.5°-210.5° C. MS M/Z: 505 (M+H). NMR: (CDCl₃ /CD₃OH) d 1.45 (s, 9H), 1.90-2.30 (m, 2H), 3.50-4.35 (m,5H) 6.91 (m, 2H),7.32 (m, 1H), 8.44 (s, 1H), 9.03 (d, 1H, J=8 Hz), 9.04 (d, 1H, J=8 Hz).IR (KBr): 1714, 1662, 1620 cm⁻¹.

EXAMPLE 1612-(3-Aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid

A 0.100 g, (0.198 mmol) sample of2-(3-(N-t-butoxycarbonyl)-aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid, from Example 160 Step 5, was dissolved in a small volume of 4N HClin dioxane and stirred at room temperature for 3 hours under a dry N₂atmosphere. The solvent was removed by evaporation under vacuum to yielda yellow solid, which was dissolved in water and neutralized to pH 7with 5% sodium bicarbonate solution,. The resulting precipitate wasfiltered off, washed with water and dried to afford 0.075 g of the titlecompound as a yellow solid mp>250° C. MS M/Z: 405 (M+H). NMR: (DMSO) d1.90-2.30 (m, 2H), 3.00-4.10 (m, 5H), 7.16 (m, 2H), 7.30 (m, 1H), 8.18(s, 1H), 9.17 (d, 1H, J=8 Hz), 9.18 (d, 1H, J=8 Hz). IR (KBr): 1715,1660 cm⁻¹. Analysis calculated for C₁₉ H₁₅ F₃ N₄ O₃.1.25 H₂ O; C, 53.46;H, 4.07; N, 13.12. Found: C, 53.64; H, 3.70; N, 12.80.

EXAMPLE 1622-(3-Aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridol[1,2-a]pyrimidine-7-carboxylicacid trifluoroacetic acid salt

A 0.879 g (2.174 mmol) sample of2-(3-aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid, from Example 161, was dissolved in 10 mL of trifluoroacetic acid,then the excess acid was removed by evaporation under vacuum. The yellowresidue was dissolved in 600 mL of water with containing 1 mL oftrifluoroacetic acid, the solution was filtered through sintered glassand freeze dried to afford 0.876 g of the title compound as a lightyellow solid; mp 191°-192° C. (dec.);. MS M/Z: 405 (M+H). NMR (CD₃ OH):∂: 0:2.102.55 (m, 2H), 3.75-4.20 (m, 5H), 7.05 (m, 2H), 7.50 (m, 1H),8.30 (s, 1H), 9.19 (d, 1H), J=8 Hz). IR (KBr): 1720, 1560, 1520 cm⁻¹.Analysis calculated for C₂₁ H₁₆ F₆ N₄ O₅.H₂ O: C, 47.02; H, 3.38; N,10.45. Found: C, 47.36; H, 3.07; N, 10.36.

EXAMPLE 1639-Cyclopropyl-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

Step 1.2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

To a 0.100 g (0.282 mmol) sample of9-cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester, prepared as described in Example 157 Step 4, wasadded 5 mL of methylene chloride, 0.275 mL of DMF and 0.33 mL ofphosphorous oxychloride, and the reaction was stirred 5 hours at roomtemperature under a dry N₂ atmosphere. The solution was cooled to 0° C.,and ice was added to destroy the excess phosphorous oxychloride. Thismixture was then extracted with methylene chloride which was dried overanhydrous magnesium surfate The solvent was removed by evaporation undervacuum to afford the title compound as an orange solid. NMR (CDCl₃): d4.27 (s, 2H), 6.83 (m, 2H), 7.27 (m, 2H), 8.48 (s, 1H). This materialwas taken directly to the next step.

Step 2.9-Cyclopropyl-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

The compound from the previous step was dissolved in 2.5 mL of methylenechloride and 0.5 mL of N-methylpiperazine was added with cooling. Thereaction was stirred at room temperature overnight. The solvent wasremoved by evaporation and the product was purified by columnchromatography on silica gel, eluting with 10% methanol in methylenechloride. The solvent was removed to afford 0.107 g of the titlecompound as a yellow solid. Recrystallization from methanol gave yellowneedles, mp 194°-195° C. MS M/Z 437 (M+H). NMR:(CDCl₃) d 0.62 (m, 2H),0.88 (m, 2H), 2.12 (m, 1H), 2.57 (s, 3H), 2.59 (t, 4 H, J=7 Hz), 4.07(t, 4H, J=7 Hz), 5.38 (s, 2H), 7.28 (m, 1H), 7.36 (m, 2H), 7.51 (m, 2H),8.04 (s, 1H), 9.16 (d, 1H, J=10 Hz). IR (KBr): 1715, 1685, 1660 cm⁻¹.Analysis calculated for C₂₄ H₂₅ FN₄ O₃. 1/4 H₂ O: C, 65.37; H, 5.83; N,12.70. Found: C, 65.21; H, 5.53; N 12.59.

Step 3.9-Cyclopropyl-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

To a 0.050 g (0.115 mmol) sample of the benzyl ester compound from theprevious step was added 10 mL of methanol, 1 mL of 98% formic acid and0.04 g of 10% Pd/C, and the mixture was stirred under Argon for 30 minat room temperature. The solution was diluted with methylene chloride,filtered through diatomaceous earth and the solvent was removed to leavea yellow residue. The product was purified by column chromatography onsilica gel, eluting with 1:10:100 acetic acid:methanol:methylenechloride. After removal of the solvent, 0.0345 g of the title compoundwas obtained as a yellow solid, mp 219°-220° C. MS M/Z 347 (M+H).NMR:(CDCl₃) d 0.67 (m, 2H), 0.95 (m, 2H), 2.18 (m, 1H), 2.39 (s, 3H),2.65 (t, 4H, J=6 Hz), 4.13 (m, 4H), 8.11 (s, 1H), 9.02 (d, 1H), J=10Hz). IR (KBr): 1720, 1660, 1620 cm⁻¹. Analysis calculated for C₁₇ H₁₉FN₄ O₃.0.6 CH₃ COOH: C, 57.17; H, 5.64; N, 14.65. Found: C, 57.60; H,5.79; N, 14.13.

EXAMPLE 1649-Cyclopropyl-3-fluoro-2-(piperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

Step 1.2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid t-butyl ester

A mixture of 0.100 g (0.312 mmol) of9-cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid t-butyl ester from Example 158 Step 1, 0.29 mL of DMF, 0.33 mL ofphosphorous oxychloride and 10 mL of methylene chloride was stirredunder a dry N₂ atmosphere at room temperature for 1 hour. After workupas described in Example 157 Step 5, the title compound was obtained as aorange solution in methylene chloride, which was taken directly to thenext step.

Step 2.9-Cyclopropyl-3-fluoro-2-(piperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid t-butyl ester

The sample from Step 1 in 5 mL of methylene chloride was added dropwiseto a solution of 0.289 g piperazine in 10 mL of methylene chloridestirred under a dry N₂ atmosphere. The resulting yellow solution wasconcentrated to give a yellow residue, which was purified by columnchromatography on silica gel, eluting with 0.5:10:100 conc. ammoniumhydroxide:methanol:methylene chloride, to afford after removal of thesolvent 0.068 g of the title compound as a yellow solid. This materialwas taken directly to the next step.

Step 3.9-Cyclopropyl-3-fluoro-2-(piperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

The sample of the compound from the previous step was reacted with 10 mLof 4N HCl in dioxane under a dry N₂ atmosphere at room temperatureovernight. The solvent was removed, the yellow solid was dissolved indistilled water, adjusted to pH 7-8 with saturated sodium carbonatesolution, and the solution extracted with methylene chloride. Theextracts were washed with water, dried, concentrated, andchromatographed on silica gel to afford 0.043 g of the title compound asa yellow solid, mp 198°-199° C. MS M/Z 333 (M+H). NMR:(CDCl₃) d 0.67 (m,2H), 0.94 (m, 2H), 2.19 (m, 1H), 3.08 (t, 4H, J=6 Hz), 4.08 (m, 4H),8.11 (s, 1H), 9.01 (d, 1H, J=10 Hz). IR (KBr): 1710, 1660 cm⁻¹. Analysiscalculated for C₁₆ H₁₇ FN₄ O₃.0.1 H₂ O: C, 57.36; H, 5.20; N, 16.72.Found: C, 57.69; H, 5.22; N, 16.31.

EXAMPLE 1659-Cyclopropyl-3-fluoro-2-(morpholin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

Step 1.9-Cyclopropyl-3-fluoro-2-(morpholin-1-yl)-6H-6-oxo-pyridol[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

To a 0.150 g (0.396 mmol) sample of2-chloro-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester, prepared as in Example 164 Step 1, dissolved inanhydrous methylene chloride and cooled to 0° C. and stirred under a dryN₂ atmosphere was added 0.042 mL (0.483 mmol) of morpholine dropwise.The color changed from orange to yellow, and the reaction was completein 15 min. The solvent was removed by evaporation, and the product waspurified by column chromatography on silica gel, eluting with 2:10:100acetic acid:methanol:methylene chloride. The solvent was removed toafford the title compound as a yellow solid. This was taken directly tothe next step. NMR:(CDCl₃) d 0.62 (m, 2H), 0.89 (m, 2H), 2.11 (m, 1H),3.87 (t, 4H), J=6 Hz), 4.07 (t, 4H, J=6 Hz), 5.39 (s, 2H), 7.29 (m, 1H),7.37 (m, 2H), 7.51 (m, 2H), 8.07 (s, 1H), 9:19 (d, 1H, J=10 Hz).

Step 2.9-Cyclopropyl-3-fluoro-2-(morpholin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid

The benzyl ester product from the previous step was dissolved in 20 mLof anhydrous methanol and stirred with 0.020 g of 10% Pd/C catalystunder 1 atm. Hydrogen at room temperature for 5 hours. The catalyst wasremoved by filtration, and the solvent was removed under vacuum toafford 0.100 g of the title compound as a yellow solid, mp>260° C. MSM/Z 334 (M+H). NMR:(CDCl₃) d 0.68 (m, 2H), 0.95 (m, 2H), 2.19 (m, 1H),3.90 (t, 4H, J=6 Hz), 4.10 (t, 4H, J=6 Hz)., 8.15 (s, 1H), 9.06 (d, 1H,J=10 Hz). IR 1720, 1660, 1620 cm⁻¹. Analysis calculated for C₁₆ H₁₆ FN₃O₄.H₂ O: C, 54.70; H, 5.16; N, 11.96. Found: C, 55.01; H, 4.71; N,11.62.

EXAMPLE 1669-(2,4-Difluorophenyl)-3-fluoro-2-(3-(N-(S)-norvalyl)aminopyrrolidin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid hydrochloride salt

Step 1.2-(3-Aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester.

A 1.579 g (2.655 mmol) sample of the9-(2,4-difluorophenyl)-3-fluoro-2-(3-(N-t-butoxycarbonyl)aminopyrrolidin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester, from Example 160 Step 4, was dissolved in 5 mL oftrifluoroacetic acid and stirred at room temperature for 1 hour under adry N₂ atmosphere. The solvent was removed by evaporation under vacuumto yield the deprotected title product as a yellow solid, which wastaken directly to the next step. Mp 185°-186° C. NMR (CDCl₃): d1.75-2.19 (m, 2H), 3.33-4.07 (m, 5H), 5.38 (s, 2H), 6.87 (m, 2H), 7.32(m, 4H), 7.48 (m, 2H), 8.33 (s, 1H), 9.13 (apparent d, 1H, J=9 Hz).

Step 2.2-(3-(N-(N-Benzyloxycarbonyl)norvalyl)aminopyrrolidin-1-yl)-9-(2,4-difluorphenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

The sample from the previous step was suspended in 50 mL of THF anddiisopropylethylamine was added with stirring at room temperature untila homogeneous solution resulted. Then 0.885 g (2.66 mmol) of theN-benzyloxycarbonyl protected (s)-norvaline succinamide was added andstirred at room temperature for 1 hour under a dry N₂ atmosphere.Another 0.050 g of the protected norvaline was added, and the solutionwas stirred for another 0.5 hours. The reaction was diluted withmethylene chloride, washed with water (4×), and the organic solventdried over anhydrous magnesium sulfate and removed by evaporation undervacuum. This product was purified by column chromatography on silicagel, eluting with 5% methanol in methylene chloride, to afford 1.678 gof the title compound as a yellow crystalline solid after removal of thesolvent. Mp 103°-105° C. MS M/Z: 728 (M+H). NMR: (CDCl₃) d 0.90 (t, 3H,J=7 Hz), 1.39-2.30 (m, 6H), 3.30-4.40 (m, 5H), 4.85-5.40 (m, 5H),6.75-7.40 (m, 13H), 8.15-8.80 (m, 2H). IR (KBr): 1700, 1660 cm⁻¹.Analysis calculated for C₃₉ H₃₆ F₃ N₅ O₆.0.25 H₂ O: C, 63.97; H, 5.02;N, 9.56. Found: C, 64.19; H 5.11; N, 9.50.

Step 3.9-(2,4-Difluorophenyl)-3-fluoro-2-(3-(N-(S)-norvalyl)aminopyrrolidin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid hydrochloride salt

A 1.515 g sample (2.0822 mmol) sample of the compound from the previousstep was dissolved in 80 mL of methanol, and 4.0 mL of 98% formic acidand 0.2 g of 10% Pd/C was added. The mixture was stirred at roomtemperature for 1.7 hours under a dry N₂ atmosphere, filtered andconcentrated to leave a yellow solid residue. This solid was dissolvedin methanol and filtered through sintered glass, then the solvent wasremoved to leave a yellow solid. This solid was dissolved in 50 mL ofmethanol, 3 mL of conc. HCl was added and the solvent evaporated off.The residue was dissolved in 200 mL of water, filtered again throughsintered glass, and the solution was freeze-dried to afford 0.969 g ofthe title product as a yellow solid, mp 192°-194° C. MS M/Z: 504 (M+H).NMR: (CD₃ OD) d 0.96 (m, 3H), 1.90-2.35 (M, 6H), 3.50-4.60 (m, 5H), 7.02(m, 2H), 7.48 (m, 1H), 8.22 (br s, 1H), 8.35 (br s, 2H), 9.09 (m, 1H).IR (KBr): 1710, 1665, 1610 cm⁻¹. Analysis calculated for C₂₄ H₂₅ F₃ N₅O₄.2 H₂ O: C, 50.05; H, 5.07; N, 12.16. Found: C, 50.00; H, 4.56; N,12.03.

EXAMPLE 1672-(3-(N-(S)-Alanyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyridol[1,2a]pyrimidine-7-carboxylicacid hydrochloride

Step 1.2-(3-(N-(N-Benzyloxycarbonyl)alanyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid benzyl ester

A 0.982 g (1.986 mmol) sample of9-(2,4-difluorophenyl)-3-fluoro-2-(3-aminopyrrolidin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester, prepared as described in Example 166 Step 1, wassuspended in 40 mL of THF and 0.700 g (2.196 mmol) of theN-benzyloxycarbonyl protected (S)-alanine succinamide was added. Themixture was stirred at room temperature for 2 hour under a dry N₂atmosphere. The reaction solvent was evaporated off, then the residuewas dissolved in methylene chloride, which was washed with water (3×).The organic solvent was dried over anhydrous magnesium sulfate andremoved by evaporation under vacuum. This product was purified by columnchromatography on silica gel, eluting with 5% methanol in methylenechloride, to afford, after removal of the solvent, 1.318 g of the titlecompound as a yellow crystalline solid, mp 104°-107° C. MS M/Z 700(M+H). NMR: (CDCl₃) d 1.43 (m, 3H), 1.95-2.30 (m, 2H), 3.40-4.40 (m,5H), 4.75-5.35 (M, 5H), 6.77 (m, 2H), 7.10-7.40 (m, 1H), 8.18-8.40 (m,2H). IR (KBr): 1720, 1660 cm⁻¹. Analysis calculated for C₃₇ H₃₂ F₃ N₅O₆. 1/2 H₂ O: C, 62.71; H, 4.69; N, 9.88. Found: C, 63.04; H, 4.49; N,9.92

Step 2.2-(3-(N-(S)-Alanyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid hydrochloride

A 1.262 g (1.804 mmol) sample of the compound from the previous step wassuspended in 80 mL of methanol and 4.0 mL of 98% formic acid and 0.200 gof 10% Pd/C was added with stirring. The mixture was stirred at roomtemperature for 1.7 hours, then 40 ml of THF was added and the mixturestirred for 0.3 hours longer under a dry N₂ atmosphere, filtered andconcentrated to leave a yellow solid residue. This was dissolved in 500mL of water and 4 mL of conc. HCl was added, then the solution wasfiltered through sintered glass and freeze-dried to afford 0.877 g ofthe title compound as a yellow solid, mp 198°-200° C. (dec). MS M/Z 476(M--Cl). NMR: (DMSO-d₆) d 1.33 (apparent t, 3H, J=7 Hz), 1.90-2.30 (m,2H), 3.35-4.40 (m, 6H), 7.17 (m, 1H), 7.32 (m, 1H), 7.58 (m, 1H), 8.20(d, 1H), 9.19 (m, 1H), 13.45 (br, 1H). IR (KBr): 1715, 1665, 1620 cm⁻¹.Analysis calculated for C₂₂ H₂₁ ClF₃ N₅ O₄.1.5 H₂ O; C, 49.03; H, 4.48;N, 12.99. Found: C, 49.18; H, 4.17; N, 12.53.

EXAMPLE 1682-(3-(N-(S)-Alanyl-(S)-alanyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid hydrochloride

Step 1.2-(3-(N-(N-Benzyloxycarbonyl)-(S)-alanyl-(S)-alanyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid benzyl ester

A 0.905 g (1.830 mmol) sample of9-(2,4-difluorophenyl)-3-fluoro-2-(3-aminopyrrolidin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester, prepared as described in Example 166 Step 1, wassuspended in 10 mL of DMF and 0.700 g (2.196 mmol) of theN-benzyloxycarbonyl protected (S)-alanyl-(S)-alanine. The mixture wasstirred at 0° C. and 0.530 g of1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDAC) and0.370 g of 1-hydroxybenzotriazole hydrate (HOBT) was added. The mixturewas stirred for 30 min at 0° C., then at room temperature for 2 hours.The solvent was removed in a kugelrohr apparatus, then the residue wasdissolved in methylene chloride, washed 2× with water, washed 2× withsaturated sodium bicarbonate solution, then 2× again with water anddried over magnesium surfate. The solvent was removed by evaporation,and the product was purified by column chromatography on silica gel,eluting with 10% methanol in methylene chloride to afford 1.187 g of thetitle product as yellow crystals, mp 123°-126° C. MS M/Z 771 (M+H). NMR:(CDCl₃) d 1.37 (m, 6H), 1.92-2.18 (m, 2H), 3.58-4.48 (m, 5H), 4.76-5.00(m, 2H), 5.30 (s, 2H), 5.32 (s, 2H), 6.80 (m, 2H), 7.10-7.45 (m, 1H),8.23 and 8.30 (two s, 1H), 8.87 and 8.93 (two d, 1H, J=8 Hz). IR (KBr):1720, 1660 cm⁻¹. Analysis calculated for C₄₀ H₃₇ F₃ N₆ O₇. 1/2 H₂ O: C,61.62; H, 4.91; N, 10.78. Found: C, 61.51; H, 4.71; N, 10.75.

Step 2.2-(3-(N-(S)-Alanyl-(S)-alanyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid hydrochloride

A 1.131 g (1.467 mmol) sample of the compound from Step 1 was dissolvedin 80 mL of methanol and 4.0 mL of 98% formic acid and 0.2 g of 10% Pd/Cwas added. The mixture was stirred 1 hour at room temperature under adry N₂ atmosphere, filtered, and concentrated to leave a yellow residue.This was dissolved in 500 mL of distilled water and 3 mL of conc. HClwas added, then the solution was filtered though sintered glass, andfreeze-dried to afford 0.729 g of the title compound as a pale yellowsolid, mp 217°-219° C. (dec). MS M/Z 547 (M-Cl). NMR: (DMSO-d₆) d 1.24(m, 3H), 1.32 (d, 3H, J=7 Hz), 1.80-2.20 (m, 2H), 3.40-4.50 (m, 7H),7.17 (m, 1H), 7.31 (m, 1H), 7.57 (m, 1H), 8.20 (br, 4H), 8.47 (m, 1H),8.66 (m, 1H), 9.19 (m, 1H), 13.45 (br, 1H). IR (KBr): 1710, 1660, 1630cm⁻¹.

EXAMPLE 1692-((2S,4S)-4-Acetamido-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid

Step 1. 2-((2S,4S)-4-Acetamido-2-methylpyrrolidin-1-yl)-9-(2,4-Ddifluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

A 0.200 g (0.469 mmol) sample of9-(2,4-difluorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester, from Example 160 Step 3, was dissolved in 5 mL ofmethylene chloride and 0.42 mL of DMF and 0.49 mL of POCl₃ were added.The reaction was stirred under a dry N₂ atmosphere at room temperaturefor 3.5 hours, then quenched with ice and water. The mixture wasextracted with methylene chloride, and the solvent was washed with wateruntil the acidity of the rinse water was above pH 3. The solvent wasthen dried with magnesium sulfate and 0.120 g (0.656 mmol) of(2S,4S)-4-acetamido-2-methylpyrrolidine (prepared as described by Rosen,T., et al., J. Med. Chem., 31, 1598-1611 (1988)) in 10 mL of methylenechloride and 2 mL of triethylamine was added and allowed to react. Thesolution was then concentrated and the product was purified by columnchromatography over silica gel eluting with 1:10:100 aceticacid:methanol:methylene chloride. The solvent was removed to afford0.205 g of the title compound as yellow crystals, mp 117°-119° C.[a]=-122.6° (25° C., D, c=0.05, CHCl₃). MS M/Z 551 (M+H). NMR: (CDCl₃) d1.10 (d, 3H, J=7 Hz), 1.85-2.25 (m, 2H), 2.10 (s, 3H), 4.05 (m, 2H),4.23 (m, 1H), 4.80 (m, 1H), 5.06 (d, 1H, J=13 Hz), 5.27 (d, 1H, J=13Hz), 6.79 (m, 2H), 7.20-7.40 (m, 6H), 7.76 (br, 1H), 8.21 (s, 1H), 8.80(d, 1H, J=9 Hz). IR (KBr): 1725, 1660 cm⁻¹. Analysis calculated for C₂₉H₂₅ F₃ N₄ O₄.H₂ O: C, 61.26; H, 4.79; N, 9.85. Found: C, 61.59; H, 4.37;N, 9.72.

Step 2.2-((2S,4S)-4-Acetamido-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid

To a 0.198 g (0.359 mmol) sample of the compound from Step 1 in 20 mL ofmethanol was added 1 mL of 98% formic acid and 0.1 g of 10% Pd/C. Themixture was stirred at room temperature under a dry N₂ atmosphere for1.25 hours. The mixture was filtered, and the filtrate concentrated toleave a yellow residue. The product was purified by columnchromatography on silica gel, eluting with 1:10:100 aceticacid:methanol:methylene chloride to afford 0.126 g of the title compoundas a yellow solid, after removal of the solvent, mp 163°-164° C.[a]=-50.2° (23° C., D, c=0.5, CHCl₃). MS M/Z 461 (M+H). NMR: (CDCl₃ +CD₃OD) d 1.09 and 1.39 (two d, 3H, J=6 Hz), 1.92-2.15 (m, 2H), 2.00 (s,3H), 3.97 (m, 1H), 4.16 (m, 1H), 4.32 (m, 1H), 4.72 (m, 1H), 6.90 (m,2H), 7.25 (m, 1H), 8.17 and 8.31 (two s, 1H), 8.93 and 8.97 (two d, 1H,J=8 Hz). IR (KBr): 1720, 1660, 1035 cm⁻¹. Analysis calculated for C₂₂H₁₉ F₃ N₄ O₄.H₂ O: C, 55.23; H, 4.42; N, 11.71. Found: C, 55.25; H,4.20; N, 11.21.

EXAMPLE 1709-(2,4-Difluorophenyl)-3-fluoro-2-(3-hydroxypyrrolidin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid

Step 1.9-(2,4-Difluorophenyl)-3-fluoro-2-(3-hydroxypyrrolidin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

A 0.200 g (0.469 mmol) sample of9-(2,4-difluorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester, from Example 160 Step 3, was dissolved in 5 mL ofmethylene chloride and 0.42 mL of DMF and 0.49 mL of POCl₃ were added.The reaction was stirred under a dry N₂ atmosphere at room temperaturefor 3.5 hours, then quenched with ice and water. The mixture wasextracted with methylene chloride, and the solvent was washed with wateruntil the acidity of the rinse water was above pH 3. The solvent wasthen dried with magnesium sulfate and 0.1 mL of 3-pyrrolidinol was addedand allowed to react. The solution was then concentrated and the productwas purified by column chromatography over silica gel eluting with1:10:100 acetic acid:methanol:methylene chloride. The solvent wasremoved to afford 0.183 g of the title compound as yellow crystals, mp105°-107° C. MS M/Z 496 (M+H). NMR: (CDCl₃) d 2.00-2.16 (m, 2H),3.55-3.68 (m, 2H), 3.96-4.16 (m, 2H), 4.18 and 4.55 (m, 1H), 5.36 and5.38 (two s, 2H), 6.90 (m, 2H), 7.30-7.48 (m, 6H, 8.33 (s, 1H), 9.08 and9.14 (two d, 1H, J=6 Hz). IR (KBr): 1725, 1690, 1660 cm⁻¹. Analysiscalculated for C₂₆ H₂₀ F₃ N₃ O₄. 3/4 H₂ O: C, 61.36; H, 4.26; N, 8.26.Found: C, 60.97; H, 3.67; N, 7.98.

Step 2.9-(2,4-Difluorophenyl)-3-fluoro-2-(3-hydroxypyrrolidin-1-yl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid

To a 0.166 g (0.334 mmol) sample of the compound from Step 1 in 20 mL ofmethanol and 15 mL of DMF was added 2 mL of 98% formic acid and 0.12 gof 10% Pd/C. The mixture was stirred at room temperature under a dry N₂atmosphere for 1.33 hours. The mixture was filtered, and the tiltrateconcentrated, removing the DMF in a kugelrohr apparatus, to leave ayellow residue. The product was purified by column chromatography onsilica gel, eluting with 1:10:100 acetic acid:methanol:methylenechloride to afford 0.088 g of the title compound as a yellow solid,after removal of the solvent, mp 168°-170° C. (dec). MS M/Z 406 (M+H).NMR: d 2.00-2.15 (m, 2H), 3.55-3.70 (m, 2H), 3.97-4.12 (m, 2H),4.50-4.60. (m, 1H), 6.93 (m, 2H), 7.35 (m, 1H), 8.43 (s, 1H), 9.01 and9.04 (two d, 1H, J=4 Hz). IR (KBr): 1715, 1665, 1625 cm⁻¹. Analysiscalculated for C₁₉ H₁₄ F₃ N₃ O₄. 1/2 H₂ O: C, 55.08; H, 3.65; N, 10.14.Found: C, 55.10; H, 3.53; N, 10.04.

EXAMPLE 171 2-((2S,4S)-4-Amino-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid hydrochloride

Step 1. (2S, 4S)-4-acetamido-2-methylpyrrolidine

A 6.000 g (24.760 mmol) sample of (2S,4S)-4-acetamido-1-(t-butoxy-carbonyl)-2-methylpyrrolidine, prepared asdescribed by Rosen, T., et al., J. Med. Chem., 31, 1598-1611 (1988), wasdissolved in 30 mL of 4N HCl in dioxane and stirred at room temperaturefor 24 hours to remove the boc group.. The solvent was removed byevaporation to give the hydrochloride salt of this compound as a whitesolid, which was taken directly to the next step.

Step 2. (2S, 4S)-4-acetamido-1-benzyl-2-methylpyrrolidine

This salt from the previous step was suspended in 27 mL of methylenechloride, 8.4 mL of triethylamine was added and the mixture stirred for10 min. Next was added 3.2 mL (26.9 mmol) of benzyl bromide and themixture heated at reflux for 5 hours. The mixture was diluted withmethylene chloride, which was washed 3× with water, dried over magnesiumsurfate, and evaporated to leave the 1-benzyl protected compound as awhite solid, which was taken directly to the next step.

Step 3. (2S, 4S)-4-amino- 1-benzyl-2-methylpyrrolidine hydrochloride

The acetyl group was removed from the compound from the previous step byheating at reflux for 6 hours in 6N HCl. Removal of the solvent gave thesolid product which was taken directly to the next step.

Step 4. (2S, 4S)-1-benzyl-4-t-butoxycarbonylamino-2-methylpyrrolidine

The sample from the previous step was dissolved in 10 mL of water and 35mL of methanol. To this solution stirred at 0° C. was added 5.2 mL oftriethylamine and 4.21 g of di-t-butyl dicarbonate. The reaction wasstirred for 2 hours at 0° C. and then at room temperature for 19 hours.The solvent was removed by evaporation, the residue dissolved inmethylene chloride, which was washed with water and concentrated. Theproduct was purified by column chromatography on silica gel, elutingwith 0.5:5:100 conc. ammonium hydroxide:methanol:methylene chloride togive the title compound as a white solid after removal of the solvent.This material was taken directly to the next step.

Step 5. (2S, 4S)-4-t-butoxycarbonylamino-2-methylpyrrolidine

The sample from the previous step was dissolved in 150 mL of methanol,0.90 g of 10% Pd/C was added and the mixture shaken under 4 atm ofhydrogen at room temperature for 13 hours. The mixture was concentrated,the catalyst was removed by filtration, and the solvent removed toafford 3.081 g of the title compound as a white solid. MS M/Z 201 (M+H).NMR (CDCl₃): d 1.15 (d, 3H, J=6 Hz), 1.44 (s, (H), 1.54-1.63 (m, 2H,1.75 (m, 1H), 2.64 (dd, 1H, J=5, J=12 Hz), 3.26 (m, 1H), 3.38 (dd, 1H,J=7, J=12 Hz), 4.12 (br, 1H), 4.63 (br, 1H). IR (KBr): 1685 cm⁻¹.

Step 6.2-(2S,4S)-4-t-butoxycarbonylamino-2-methylpyrrolidin-1-yl)-9-(2.4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid benzyl ester

A 1.500 (3.518 mmol) sample of9-(2,4-difluorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester, from Example 160 Step 3, was dissolved in 40 mL ofmethylene chloride and 3.20 mL of DMF and 3.70 mL of POCl₃ were added.The reaction was stirred under a dry N₂ atmosphere at room temperaturefor 2.25 hours, then quenched with ice and water. The mixture wasextracted with methylene chloride, and the solvent was washed with wateruntil the acidity of the rinse water was above pH 3. The solvent wasthen dried with magnesium sulfate and 1.06 g (0.656 mmol) of(2S,4S)-4-t-butoxycarbonylamino-2-methylpyrrolidine, from Step 5 above,in 50 mL of methylene chloride and 7 mL of triethylamine was added andallowed to react. The solution was then concentrated and the product waspurified by column chromatography over silica gel eluting with0.5:10:100 conc. ammonium hydroxide:methanol:methylene chloride. Thesolvent was removed to afford 1.856 g of the title compound as yellowcrystals, mp 106°-107° C. [a]=+13.4 (23°, D, c=0.5, CHCl₃). MS M/Z 609(M+H). NMR: (CDCl₃) d 1.11 (two d, 3H, J=7 Hz), 1.45 and 1.55 (two s,9H), 1.90-2.10 (m, 2H), 3.60-4.60 (m, 5H), 5.39 (s, 1H), 6.89 (m, 2H),7.34-7.50 (m, 6H), 8.34 and 8.36 (two s, 1H), 9.16 and 9.19 (two d, 1H,J=9 Hz). IR (KBr): 1715, 1690, 1660 cm⁻¹. Analysis calculated for C₃₂H₃₁ F₃ N₄ O₅. 1/2 H₂ O: C, 62.23; H, 5.22; N, 9.07. Found: C, 62.44; H,5.20; N, 9.16.

Step 7.2-((2S,4S)-4-Amino-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid

To a 1.814 g (2.981 mmol) sample of the compound from Step 6 dissolvedin 80 mL of methanol and 10 mL of THF was added 8 mL of 98% formic acidand 1 g of 10% Pd/C. The mixture was stirred at room temperature under adry N₂ atmosphere for 2.3 hours. The mixture was filtered, and thefiltrate concentrated to leave a yellow residue. The product waspurified by column chromatography on silica gel, eluting with 1:10:100acetic acid:methanol:methylene chloride to afford 1.513 g of the titlecompound as a yellow solid, after removal of the solvent. The compoundwas taken directly to the next step.

Step 8.2-((2S,4S)-4-Amino-2-methylpyrrolidin-1-yl)-9-(2.4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid hydrochloride

The 1.528 g sample of the compound from the previous step was dissolvedin 20 mL of 4N HCl in dioxane and stirred at room temperature for 3.5hours. The solvent was removed, the residue redissolved in 500 mL ofwater, 0.5. mL of conc. HCl was added, and the solution freeze-dried toafford 1.147 g of the title compound as a yellow solid, mp 204° C.(dec). [a]=+35.4° (22° C., D, c=0.5, CH₃ OH). MS M/Z 419 (M--Cl). NMR:(CD₃ OD) d and 1.41 (two d, 3H, J=7 Hz), 2.15-2.31 (m, 2H), 3.75-4.40(m, 4H), 7.04 (m, 2H), 7.46 (m, 1H), 8.25 and 8.30 (two s, 1H), 9.11 and9.21 (two d, 1H, J=9 Hz). IR (KBr): 1710, 1660, 1630 cm⁻¹. Analysiscalculated for C₂₀ H₁₈ F_(3Cl) N₄ O₃.H₂ O: C, 50.80; H, 4.26; N, 11.85.Found: C, 50.98; H, 4.10; N, 11.85.

EXAMPLE 1722-(3-Aminopyrrolidin-1-yl)-3-fluoro-9-(2,3,4,5,6-pentafluorophenyl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid hydrochloride salt

Step 1. 2-(2,3,4,5,6-Pentafluorophenyl)-acetamidine hydrochloride

Into a solution of 26.72 g (0.129 mol) of pentafluoroacetonitrile(commercially available) in 8.30 mL of anhydrous ethanol cooled to 0° C.and stirred under a dry N₂ atmosphere was introduced gaseous HCl, untilthe mixture solidified. The reaction was allowed to stand for 96 hours,then 60 mL of ethanol and 30.7 mL of 4.2N HCl in ethanol (0.124M) wasadded, and the slurry was stirred at room temperature for 2 hours. Themixture was faltered through sintered glass, and the filtrate wasconcentrated under vacuum to afford the title compound as a brownishsolid, which was taken directly to the next step.

Step 2. 5-Fluoro-4-hydroxy-2-(2,3,4,5,6-pentafluorobenzyl)pyrimidine

A mixture of the compound (0.129 tool) from Step 1, 0.135 mol of thesodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (prepared asdescribed by E. Elkik and M. Imbeaux-Oudotte, Bull. Soc. Chim. Fr., 5-6pt 2, 1165 (1975)), 150 mL of anhydrous methanol and 25 mL oftriethylamine was stirred under a dry N₂ atmosphere for 24 hours. Thesolvent was removed by evaporation under vacuum and the residue wasdissolved in methylene chloride and washed (1×) with 10% HCl and (1×)with water, then dried over anhydrous magnesium sulfate, and the solventwas removed by evaporation under vacuum to give a dark oil whichsolidified upon standing. This solid was washed with 1:2 ethylacetate:hexane to afford 4.843 g of the title compound as a white solid,mp 161°-162° C. The filtrate was concentrated and extracted with 1:4ethyl acetate:hexane to leave a second crop of 4.454 g of product.Additional product was obtained by chromatography of the residue, for atotal yield of 19.20 g of product. MS M/Z 312 (M+NH₄). NMR (CDCl₃): d4.15 (apparent s, 2H), 7.80 (d, 1H, J=3 Hz), 13.38 (br s, 1H). IR (KBr):3440, 1685, 1660, 1610 cm⁻¹.

Step 3.2-Ethoxy-3-(5-fluoro-4-hydroxy-3-(2,3,4,5,6-pentafluorophenyl)propane-1,1-dicarboxylicacid diethyl ester

The compound from Step 2 above (0.294 g, 1.00 mmol) was dissolved in 10mL of THF and cooled to -78° C. with stirring, then 0.82 mL (2.05 mmol)of a 2.5M solution of n-butyllithium in hexane was added and theresulting yellow solution was stirred for 30 min. To this was added0.243 mL (1.2 mmol) of ethyl 2-carboethoxy-3-ethoxy-2-propenecarboxylatewith stirring for 15 min. The reaction was quenched with 10% HCl,allowed to warm to room temperature and extracted with ethyl acetate.The extract was washed (2×) with brine, and the solvent dried overmagnesium sulfate and concentrated to afford the title compound as anoil, which was taken directly to the next step.

Step 4.9-(2,3.4.5.6-pentafluorophenyl)-3-fluoro-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid ethyl ester

The compound from Step 3 above was dissolved in 10 mL of ethanol, 0.2 mLof conc. sulfuric acid was added and the solution was heated at refluxfor 18 hours. The solvent was removed and the residue washed with etherto afford 0.222 g of the title compound as a yellow solid, mp 235-236 C.MS M/Z 419 (M+H), 436 (M+NH₄). IR (KBr): 3440 (br), 1710, 1680, 1615cm⁻¹. NMR (CDCl₃) d 1.38 (t, 3H), J=7 Hz), 4.37 (q, 2H, J=7 Hz), 8.23(s, 1H), 9.05 (d, 1H, J=6 Hz).

Step 5.3-Fluoro-2-hydroxy-9-(2.3,4.5.6-pentafluorophenyl)-6H-6-oxopyridol[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

A 1.000 g (2.391 mmol) sample of the compound from Step 4 was dissolvedin 25 mL of benzyl alcohol, 0.09 mL of titanium tetraethoxide was addedand the mixture was stirred at 90° C. for 20 hours. The reaction wasdiluted with methylene chloride, washed (1×) with 10% HCl andconcentrated in a rotary evaporator. The crude product was purified in akugelrohr apparatus to yield a yellow solid, which was washed with etherand dried to afford 0.457 g of the title compound, which was takendirectly to the next step.

Step 6.2-(3-(N-t-Butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluoro-9-(2,3,4,5,6-pentafluorophenyl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

A 0.400 g (0.833 mmol) sample of the compound from Step 5 was dissolvedin 10 mL of methylene chloride and 0.746 mL of DMF, and 0.870 mL ofPOCl₃ were added and stirred under a dry N₂ atmosphere at roomtemperature for 1.7 hours. The reaction was quenched with ice and themixture extracted with methylene chloride which was washed (2×) withwater. The organic layer was added to a stirred solution of 0.235 g (1.2mmol) of 2-(N-t-butoxycarbonylamino)pyrrolidine in 4 mL oftriethylamine. The solvent was removed by evaporation, and the productwas purified by column chromatography on silica gel, eluting with2.5:100 methanol:methylene chloride. Removal of the solvent afforded0.353 g of the title product as a yellow crystalline solid, mp 107°-108°C. MZ M/Z 649 (M+H). NMR (CDCl₃) d 1.44 (s, 9H), 1.90-2.30 (m, 2H),3.40-4.65 (m, 5H), 5.38 (s, 2H), 7.35 (m, 3H), 7.48 (m, 2H), 8.34 (s,1H), 9.14 and 9.15 (two d, 1H, J=9 Hz).

Step 7.2-(3-(N-t-Butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluoro-9-(2,3,4,5,6-pentafluorophenyl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid

A 0.335 g (0.516 mmol) sample of the compound from Step 6 was dissolvedin 40 mL of dry methanol, and the benzyl ester was removed by reactingwith 2.0 mL of 98% formic acid in the presence of 0.100 g of 10% Pd/C,stirring under a dry N₂ atmosphere for 0.0.25 hours. After filtrationand evaporation of the solvent, the product was purified by columnchromatography on silica gel, eluting with 1:15:100 aceticacid:methanol:methylene chloride to afford, after removal of thesolvent, the title compound as a yellow solid, which was taken directlyto the next step.

Step 8.2-(3-Aminopyrrolidin-1-yl)-3-fluoro-9-(2,3,4,5,6-pentafluorophenyl)-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid hydrochloride salt

The compound from the previous step was dissolved in 10 mL of 4N HCl indioxane and stirred at room temperature for 0.7 hours, after which thesolvent was removed under vacuum. The residue was dissolved in waterwhich was filtered through sintered glass and freeze-dried to afford0.232 g of the title compound as a yellow solid, mp 202°-204° C. MS M/Z459 (M--Cl). NMR (CD₃ OD): d 2.12-2.54 (m, 2H), 3.70-4.36 (m, 5H), 8.42(s, 1H), 9.21 (d, 1H, J=9 Hz). IR (KBr): 1715, 1660, 1630 cm⁻¹. Analysiscalculated for C₁₉ H₁₂ F₆ N₄ O₃.HCl.0.5 H₂ O: C, 45.30; H, 2.80; N,11.12. Found: C, 45.46; H, 2,39; N, 10.57.

EXAMPLE 173 2-((2S,4S)-4-(N-(S)-Alanyl-(S)-alany)amino-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl))-3-fluoro-6H-6-oxopyrido[1.2-a]pyrimidine-7-carboxylicacid hydrochloride

Step 1.2-((2S,4S)-4-amino-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

Following the procedure described in Example 166 Step 1, replacing theboc-protected benzyl ester compound with a 2.345 mmol sample of2-((2S,4S)-4-t-butoxycarbonylamino-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester, from Example 171 Step 6, the boc protecting group wasremoved to afford 1.06 g of the title compound.

Step 2. 2-((2S, 4S)-4-(N-(NBenzoyloxycarbonyl)-(S)-alanyl-(S)-alanyl)amino-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid benzyl ester

Following the procedure of Example 168 Step 1, replacing the benzylester compound of that example with 1.06 g of the compound from Step 1above, 0.98 g of the title compound was prepared.

Step 3. 2-((2S,4S)-4-(N-(S)-Alanyl-(S)-alanyl)amino-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid hydrochloride

Following the procedure of Example 168 Step 2, replacing theboc-protected benzyl ester compound of that example with the compoundfrom Step 2 above, 0.66 g of the title compound was prepared. Mp198°-200° C. MS M/Z 561 (M--Cl). NMR (CD₃ OD): d 1.14 and 1.40 (two d,3H, J=7 Hz), 1.34 and 1.35 (two d, 3H, J=7 Hz), 1.50 and 1.51 (two d,3H, J=7 Hz), 1.96-2.11 (m, 2H), 3.50-4.60 (m, 6H), 7.40 (m, 2H), 7.47(m, 1H), 8.26 and 8.29 (two s, 1H), 9.12 and 9.16 (two d, 1H, J=9 Hz).

EXAMPLE 1749-(2,4-Difluorophenyl)-3-fluoro-2-hydroxy-4-methyl-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid ethyl ester

Step 1. 2-(2,4-Difluorobenzyl)-5-fluoro-4-hydroxy-6-methylpyrimidine

A mixture of 8.6 g (0.0445 mmol) of 2-(2,4-difluorophenyl)-acetamidinehydrochloride, prepared as in Example 159 Step 1, and 6.1 g (0.0405mmol) of ethyl 2-fluoro-3oxo-butanoate (prepared as described by E. O.Bergmann, S. Cohen, and I. Shahak, J. Chem. Soc., 3278₋₋ (1959)), in 30mL of anhydrous methanol and 10.1 mL of a 2.5% solution of sodiummethoxide was heated at reflux under a dry N₂ atmosphere for 16 hours.The solvent was removed by evaporation under vacuum, and the residue waswashed with water, then 200 mL of water added and the mixture wasacidified and the resulting precipitate was filtered off. The aqueoussolution was then extracted (3×) with methylene chloride. The solventwas washed with water, dried over anhydrous magnesium sulfate, and thesolvent was removed by evaporation under vacuum to give a dark solid.The solid was washed with ethyl ether and dried, then combined with theearlier precipitate which was recrystallized from methanol:ether toafford 4.51 g of the title compound. MS M/Z 272 (M+NH₄). NMR: (CDCl₃) d2.22 (d, 3H, J=4 Hz), 3.92 (s, 2H), 6.92 (m, 2H), 7.30 (m, 1H).

Step 2.3-(2,4-Difluorophenyl)-2-ethoxy-3-(5-fluoro-4-hydroxy-6-methylpyrimidin-2-yl)propane-1,1-dicarboxylic acid diethyl ester

A 0.615 g (2.42 mmol) sample of the compound from Step 1 above wasdissolved in THF and cooled to -78° C. with stirring under a dry N₂atmosphere. To this was slowly added 1.98 mL of 2.5N n-butyllithium inhexane, and the mixture was stirred for 30 min. Then 0.586 mL (2.9 mmol)of diethyl ethoxymethylenemalonate was added at -78° C. and the mixturestirred for an additional 15 min at room temperature. The reactionmixture was quenched with 10% HCl until the mixture was about pH 3,whereupon it was then extracted with ethyl acetate. This was dried overanhydrous magnesium sulfate, and the solvent was removed by evaporationunder vacuum to afford 1.6 g of the title compound as a yellow oil. Thismaterial was taken directly to the next step.

Step 3.9-(2,4-Difluorophenyl)-3-fluoro-2-hydroxy-4-methyl-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylicacid ethyl ester

The compound from Step 2 was dissolved in toluene, 0.62 mL of DBU wasadded and the mixture heated at reflux in a flask equipped with aDean-Stark condenser for 16 hours under a dry N₂ atmosphere. The mixturewas removed from the heat and stirred with 70 mL of water for 2 hours.After separation, the organic phase was dried over magnesium sulfate,and the solvent was removed by evaporation. The residue was purified bycolumn chromatography on silica gel, eluting with 1:5:100 aceticacid:methanol:methylene chloride to afford 0.175 g of the title compoundas a yellow solid. MS M/Z: 379 (M+H). NMR:(DMSO-d₆) d 1.21 (t, 3H, J=7Hz), 2.07 (d, 3H, J=4 Hz), 4.10 (q, 2H, J=7 Hz), 7.03 (m, 1H), 7.16 (m,1H), 7.38 (m, 1H), 7.66 (s, 1H).

EXAMPLES 175-178

By following the procedures described in Example 174 and substitutingthe appropriate ester for ethyl 2-fluoro-3-oxobutyrate, Examples 175-178may be prepared as disclosed in Table 6 (where R=ethyl and R¹=2,4-difluorophenyl).

                  TABLE 6                                                         ______________________________________                                         ##STR107##                                                                   Example No.         R.sup.5                                                   ______________________________________                                        175                 CH.sub.2 CH.sub.2 F                                       176                 CH.sub.2 F                                                177                 CHF.sub.2                                                 178                 CF.sub.3                                                  ______________________________________                                    

EXAMPLES 179-195

By following the procedures described in Example 160 Steps 3, 4 and 5and Example 161, and replacing 2-(N-t-butoxycarbonylamino)pyrrolidine inStep 4 with the appropriate N-methyl- or boc-protected amine, Examples179-195 _may be prepared as disclosed in Table 7 (where R¹=2.4-difluorophenyl).

                  TABLE 7                                                         ______________________________________                                         ##STR108##                                                                   Example No.  R.sup.2         R.sup.5                                          ______________________________________                                                                     CH.sub.3                                         179                                                                                         ##STR109##                                                      180                                                                                         ##STR110##     CH.sub.3                                         182                                                                                         ##STR111##     CH.sub.2 F                                       183                                                                                         ##STR112##     CF.sub.3                                         184                                                                                         ##STR113##     CH.sub.3                                         185                                                                                         ##STR114##     CH.sub.2 F                                       186                                                                                         ##STR115##     CHF.sub.2                                        187                                                                                         ##STR116##     CF.sub.3                                         188                                                                                         ##STR117##     CH.sub.3                                         189                                                                                         ##STR118##     CH.sub.2 F                                       190                                                                                         ##STR119##     CHF.sub.2                                        191                                                                                         ##STR120##     CF.sub.3                                         192                                                                                         ##STR121##     CH.sub.3                                         193                                                                                         ##STR122##     CH.sub.2 F                                       194                                                                                         ##STR123##     CH.sub.2 F                                       195                                                                                         ##STR124##     CF.sub.3                                         ______________________________________                                    

EXAMPLES 196-240

By following the procedures described in Example 160 Steps 3, 4 and 5and Example 161, replacing 2-(N-t-butoxycarbonylamino)pyrrolidine inStep 4 with the appropriate substituted or boc-protected amine andreplacing 9-(2,4-difluoro-phenyl)-3-fluoro-2-hydroxy-6H-6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid benzyl ester with the compoundcontaining the appropriate R¹ group (as described in Examples 2 and 39),Examples 196-240 may be prepared as disclosed in Table 8.1 to 8.3 inwhich: R¹ is 4-fluorophenyl (Table 8.1), 2,4-difluorophenyl (Table 8.2)or cyclopropyl (Table 8.3); and R⁵ is hydrogen.

                  TABLE 8.1                                                       ______________________________________                                         ##STR125##                                                                   R.sup.1 = 4-fluorophenyl, R.sup.5 = H:                                        Example No.  R.sup.2                                                          ______________________________________                                        196                                                                                         ##STR126##                                                      197                                                                                         ##STR127##                                                      198                                                                                         ##STR128##                                                      199                                                                                         ##STR129##                                                      200                                                                                         ##STR130##                                                      201                                                                                         ##STR131##                                                      202                                                                                         ##STR132##                                                      203                                                                                         ##STR133##                                                      204                                                                                         ##STR134##                                                      205                                                                                         ##STR135##                                                      206                                                                                         ##STR136##                                                      207                                                                                         ##STR137##                                                      208                                                                                         ##STR138##                                                      209                                                                                         ##STR139##                                                      210                                                                                         ##STR140##                                                      ______________________________________                                    

                  TABLE 8.2                                                       ______________________________________                                         ##STR141##                                                                   R.sup.1 = 2,4-difluorophenyl, R.sup.5 = H:                                    Example No.  R.sup.2                                                          ______________________________________                                        211                                                                                         ##STR142##                                                      212                                                                                         ##STR143##                                                      213                                                                                         ##STR144##                                                      214                                                                                         ##STR145##                                                      215                                                                                         ##STR146##                                                      216                                                                                         ##STR147##                                                      217                                                                                         ##STR148##                                                      218                                                                                         ##STR149##                                                      219                                                                                         ##STR150##                                                      220                                                                                         ##STR151##                                                      221                                                                                         ##STR152##                                                      222                                                                                         ##STR153##                                                      223                                                                                         ##STR154##                                                      224                                                                                         ##STR155##                                                      225                                                                                         ##STR156##                                                      ______________________________________                                    

                  TABLE 8.3                                                       ______________________________________                                         ##STR157##                                                                   R.sup.1 = cyclopropyl, R.sup.5 = H:                                           Example No.  R.sup.2                                                          ______________________________________                                        226                                                                                         ##STR158##                                                      227                                                                                         ##STR159##                                                      228                                                                                         ##STR160##                                                      229                                                                                         ##STR161##                                                      230                                                                                         ##STR162##                                                      231                                                                                         ##STR163##                                                      232                                                                                         ##STR164##                                                      233                                                                                         ##STR165##                                                      234                                                                                         ##STR166##                                                      235                                                                                         ##STR167##                                                      236                                                                                         ##STR168##                                                      237                                                                                         ##STR169##                                                      238                                                                                         ##STR170##                                                      239                                                                                         ##STR171##                                                      240                                                                                         ##STR172##                                                      ______________________________________                                    

EXAMPLES 241-250

By following the procedures of Example 157 Steps 2-8, replacing2-cyclopropyl-2-ethoxycarbonylacetamidine hydrochloride in Step 2 withthe compound containing the appropriate R¹ group (refer to compound 6Bin Scheme II), and replacing the 3-(N-t-butoxycarbonyl)aminopyrrolidinein Step 6 with the appropriately protected amine, Examples 241-250 maybe prepared as disclosed in Table 9, above, (in which R⁵ is hydrogen).

                  TABLE 9                                                         ______________________________________                                         ##STR173##                                                                   Example No.  R.sup.2      R.sup.1                                             ______________________________________                                        241                                                                                         ##STR174##                                                                                 ##STR175##                                         242                                                                                         ##STR176##                                                                                 ##STR177##                                         243                                                                                         ##STR178##                                                                                 ##STR179##                                         244                                                                                         ##STR180##  F.sub.3 C                                           245                                                                                         ##STR181##  FCH.sub.2 CH.sub.2                                  246                                                                                         ##STR182##                                                                                 ##STR183##                                         247                                                                                         ##STR184##                                                                                 ##STR185##                                         248                                                                                         ##STR186##                                                                                 ##STR187##                                         249                                                                                         ##STR188##  F.sub.3 C                                           250                                                                                         ##STR189##  FCH.sub.2 CH.sub.2                                  ______________________________________                                    

EXAMPLES 251-252

By following the procedures of Example 157, steps 2-8, replacingreplacing 2-cyclopropyl-2-ethoxycarbonylacetamidine hydrochloride inStep 2 with2-(N-benzoyloxycarbonyl-N-methylamino)-2-ethoxycarbonylacetamidinehydrochloride, and replacing the 3-(N-t-butoxycarbonyl)aminopyrrolidinein Step 6 with the appropriately protected amine, Examples 251-252 maybe prepared as disclosed in Table 10 (in which R⁵ =H).

                  TABLE 10                                                        ______________________________________                                         ##STR190##                                                                   Example No.   R.sup.2      R.sup.1                                            ______________________________________                                        251                                                                                          ##STR191##  CH.sub.2 NH                                        252                                                                                          ##STR192##  CH.sub.3 NH                                        ______________________________________                                    

EXAMPLES 2538-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid

Step 253a. 4-t-Butoxy-3-chloro-2,5,6-trifluoropyridine

To 250 mL of a THF solution containing 106 g (0.571 mmol) of a mixtureof 4-chlorotetrafluoropyridine and 3-chloro-tetrahydropyridine (approx70:30 ratio, from Aldrich Chemical Co.) at -78° C. was added a solutionof 38.3 g (0.399 mmol) of sodium t-butoxide in 350 mL of THF, and thesolution was stirred for 2 hours at -78° C. and at ambient temperaturefor 16 hours. The mixture was poured into 500 mL of hexane, and thismixture was filtered through celite and the filtrate concentrated. Theresidue was purified by flash chromatography, eluting first with hexane,then ethyl acetate:hexane (1:4), to separate the desired title productfrom the mixture of products. MS 238, 240 (M+H)⁺ ; 1H NMR (CDCl₃) ∂:1.52 (d, J=2 Hz); ¹⁹ F NMR (CDCl₃, CFCl₃ as reference) ∂: 73.75 (dd, J₁=14.2, J₂ =23.2 Hz), 89.71 (dd, J₁ 14.2, J₂ =21.98 Hz); 152.42 (apparentt, J=22 Hz).

Step 253b. 4-t-Butoxy-2,3,6-trifluoropyridine

To the product from Step 253a above (24.92 g, 0.104 mmol) in 100 mL ofmethanol was added 2.5 g of Pearlman's catalyst (Aldrich Chemical Co.),and the mixture was stirred at ambient temperature for 14 hours underand atmosphere of hydrogen. An additional 2.5 g of catalyst was added,and the mixture was stirred for another 22 hours. The mixture wasfiltered, the filtrate was concentrated, and the residue was extractedwith hexane/ether. After filtration, the solvent was removed byevaporation, and the residue was purified by flash chromatography (ethylacetate:hexane 1:16) to yield 12.05 g of the title product. MS 206(M+H)⁺, 233 (M+18)⁺ ; 1H NMR (CDCl₃) ∂: 1.52 (s, 9H), 6.51 (m, 1H); ¹⁹ FNMR (CDCl₃, CFCl₃ as reference) ∂: 72.60 (dd, J₁ =14.3, J₂ =21.0 Hz),89.74 (dd, J₁ =14.3, J₂ =21.0 Hz), 164.68 (dt, J₁ =4.2, J₂ =21.0 Hz).

Step 253c. 4-t-Butoxy-2,3,6-trifluoro-5-methylpyridine

A fleshly prepared solution of lithium diethylamide (LDA) (58.21 mmol)in 30 mL of THF at -78° C. was added to 10.0 g (48.74 mmol) of theproduct from Step 253b in 50 mL of THF at -78° C., and the reaction wasstirred for 50 min. To the reaction mixture was added 4.3 mL (69.07mmol) of methyl iodide, and the mixture was stirred at -78° C. for 1hour and stirred at ambient temperature for 16 hours. The reaction wasquenched with saturated NH₄ Cl solution, extracted with hexane, and theextracts washed with water, dried over MgSO4 and concentrated to givethe title product as a pale yellow oil, which was taken directly to thenext step. MS (220) (M+H)⁺ ; 1H NMR (CDCl₃) ∂: 1.47 (m, 9H), 2.12 (m,3H). ¹⁹ F NMR (CDCl₃, CFCl₃ as reference) ∂: 75.91 (dd apparent, J₁=15.0, J₂ =22.1 Hz), 93.17 (dd apparent, J₁ =15.0, J₂ =22.1 Hz), 156.54(m).

Step 253d. 4-t-Butoxy-2,5-difluoro-3-methylpyridine

A sample of the product from Step 253c above (48.74 mmol) and 13.5 mL ofhydrazine monohydrate were dissolved in 150 mL of n-propanol. Thereaction was stirred at reflux temperature under nitrogen for 4 hours.The volatiles were removed, and the residue was dissolved in methylenechloride, which was washed with water and dried over MgSO₄. The solventwas removed to give the intermediate hydrazine product as a yellowliquid, which was dissolved in 110 mL of methanol. To this was added 20mL of 20% NaOH and air was passed through the solution for 16 hours. Thesolvents were removed at 30° C. under vacuum. The residue was dissolvedin methylene chloride, which was washed with water and dried over MgSO₄.The solvent was removed and the crude product purified by flashchromatography, eluting with ethyl acetate:hexane 1:16 to give the titleproduct as a colorless liquid after removal of the solvents. MS (202)(M+H)⁺ ; 1H NMR (CDCl₃) ∂: 1.43 (d, 9H, J=1.5 Hz), 2.18 (d, 3H, J=1.5Hz), 7.85 (br s, 1H); ¹⁹ F NMR (CDCl₃, CFCl₃ as reference) ∂: 73.37 (d,J=24.5 Hz), 142.17 (d, J=24.5 Hz).

Step 253e.2-(4-t-Butoxy-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile

A sample of the product from Step 253d above (40.8 mmol) was dissolvedin 50 mL of THF and cooled to -78° C. To this was added a fleshlyprepared solution of LDA (0.103 mmol) in 50 mL of THF at -78° C., andthe reaction was stirred for 1 hour. The reaction was then stirred at 0°C. for 1 hour, quenched with saturated NH₄ Cl solution and extractedwith ether. The extracts were washed with saturated NaCl solution, driedover MgSO₄, and concentrated. The residue was purified by flashchromatography, eluting with 1:4 ethyl acetate:hexane, to yield 10.33 gof the title product after removal of the solvent. MS 263 (M+H)⁺ ; 1HNMR (CDCl₃) ∂: 0.50 (m, 2H), 0.63 (m, 1H), 0.73 (m, 1H), 1.60 (m, 1H),1.43 (d, 9H, J=2 Hz), 2.29 (s, 3H), 3.76 (d, 1H, J=8 Hz), 8.30 (d, 1H,J=3 Hz). IR (neat) 2240, 1580, 1470 cm⁻¹.

Step 253f.2-(4-Chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile

A sample of the product from Step 253e above (5.21 g, 19.86 mmol) wasdissolved in 50 mL of trifluoroacetic acid, the reaction was stirredunder nitrogen for 1 hour at ambient temperature, and the materialconcentrated to dryness. The residue was dissolved in a mixture of 15.6mL of DMF and 90 mL of methylene chloride. This solution was cooled in awater bath as 18.8 mL (19.86 mmol) of POCl₃ was added, then the reactionwas stirred at ambient temperature for 16 hours. The reaction wasquenched by pouring it into ice water, and the mixture was extractedwith methylene chloride. The aqueous solution was adjusted to pH7 withNaOH and re-extracted with methylene chloride. The extracts werecombined and washed with water, dried over MgSO₄ and concentrated. Theresidue was purified by flash chromatography with 1:4 ethylacetate:hexane to give 3.26 g of the title product as a colorless liquidafter removal of the solvents. MS 225, 227 (M+H)⁺ ; 1H NMR (CDCl₃) ∂:0.48 (m, 1H), 0.59 (m, 1H), 0.66 (m, 1H), 0.77 (m, 1H), 1.50 (m, 1H),2.48 (s, 3H), 3.80 (d, 1H, J=8 Hz), 8.39 (s, 1H). IR (neat) 2240, 15701460 cm⁻¹.

Step 253g. Ethyl2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetate

A sample of the product from Step 253f above (3.26 g, 14.51 mmol) wasdissolved in 10 mL of ethanol, and gaseous HCl was introduced until 4 ghad been dissolved. The solution was heated to reflux, and 0.36 mL ofwater was added, then the mixture was stirred for 1 hour. The reactionwas cooled, then poured into water, and the mixture was adjusted to pH7with NaHCO₃. The mixture was then extracted with methylene chloride,which was washed with water, dried over MgSO₄ and concentrated. Theresidue was triturated with 1:4 ethyl acetate:hexane, and filtered. Thefiltrate was concentrated and the residue was purified by flashchromatography with 1:4 ethyl acetate:hexane to give 2.262 g of thetitle product after removal of the solvent. MS 272, 274 (M+H)⁺ ; 1H NMR(CDCl₃) ∂: 0.12 (m, 1H), 0.38 (m, 1H), 0.53 (m, 1H), 0.76 (m, 1H), 1.20(t, 3H, J=7 Hz), 1.67 (m, 1H), 2.40 (s, 3H), 3.23 (d, 1H, J=9 Hz), 4.16(q, 2H, J=7 Hz), 8.36 (s, 1H).

Step 253h.2-(4-Chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropane-acetaldehyde

A sample of the product from Step 253g above (1.73 g, 6.37 mmol) wasdissolved in 10 mL of THF and stirred with water bath cooling and 3.2mmol of LiAlH₄ (LAH) was added. The mixture was stirred at ambienttemperature for 1 hour, then poured into water. This mixture wasextracted with ether, the extracts were washed, dried and concentratedto give 1.48 g of a colorless oil. This oil was dissolved in 10 mL ofmethylene chloride and added to a solution of 3.8 mL (7.6 mmol) ofoxalyl chloride and 1.1 mL of DMSO (15.5 mmol) in 15 mL of methylenechloride stirred at -78° C. The solution was stirred for 15 min, and 4.4mL (31.6 mmol) of triethylamine was added. The stirring was continued at-78° C. for 5 min and at -10° C. for 10 min. The reaction was quenchedwith water, and extracted with methylene chloride. The extract waswashed, dried and concentrated to give 1.49 g of the crude titleproduct, which was taken directly to the next step without furtherpurification. MS 228, 230 (M+H)⁺ ; 1H NMR (CDCl₃) ∂: 0.25 (m, 1H), 0.35(m, 1H), 0.60 (m, 1H), 0.75 (m, 1H), 1.53 (m, 1H), 2.38 (s, 3H), 3.19(dd, 1H, J=3, J=9 Hz), 8.37 (s, 1H), 9.86 (d, 1H, J=3 Hz).

Step 253i. 8-Chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester

A sample of the product from Step 253h above (6.37 mmol) was dissolvedin 50 mL of ethanol, and to this were added 1.5 mL of piperidine, 1.5 mLof acetic acid, and 5 mL of diethyl malonate (32.9 mmol). The reactionwas heated at reflux under nitrogen for 4 hours. The solvents were thenremoved, and the residue was dissolved in ether. The ether was washedwith water and brine, then dried over MgSO₄ and concentrated.Purification in a kugelrohr apparatus gave 2.4 g of the crudecondensation product. This intermediate product was dissolved in 20 MLof of Dowtherm A™, and this solution was added to 100 mL of Dowtherm A™heated to 235° C. The reaction was then stirred at 220° C. for 45 min.After cooling, the product was separated from the solvent by flashchromatography, eluting with hexane to remove the solvent and then with1:4 ethyl acetate hexane to remove the product. In this manner 1.065 gof the title product was obtained after removal of the solvent. MS 324,326 (M+H)⁺ ; 1H NMR (CDCl₃) ∂: 0.75 (m, 2H), 1.07 (m, 2H), 1.42 (t, 3H,J=7 Hz), 2.31 (m, 1H), 3.08 (s, 3H), 4.42 (q, 2H, J=7 Hz), 8.40 (s, 1H),9.44 (d, 1H, J=6 Hz).

Step 253j.8-(3-(N-BOC-amino)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester

A sample of the product from Step 253i above (0.500 g, 1.544 mmol) wasdissolved in 20 mL of anhydrous acetonitrile, and 0.600 g of sodiumbicarbonate and 0.600 g (3.22 mmol) of 3(S)-(BOC-amino)pyrrolidine wereadded. The mixture was heated at reflux under nitrogen for 7 hours, thenthe solvent was removed and the residue was redissolved in methylenechloride. This solution was washed with water, 5% HCl, water, andconcentrated. The residue was purified by flash chromatography, elutingwith 100:10 methylene chloride:methanol, followed by 100:10:0.5methylene chloride: methanol:NH₄ OH. Removal of the solvent gave 0.778 gof the title product, which was taken directly to the next step.

Step 253k.8-(3-(N-BOC-amino)pyrrolidinyl)-1-cyclopropyl-7-fiuoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid

A sample of the product from Step 253j above (0.778 g, 1.645 mmol) wasdissolved in 20 mL of THF, 0.570 g of LiOH.H20 and 10 mL of water wereadded, and the mixture was stirred under nitrogen for 3 hours. The THFwas removed under vacuum, and the residue was adjusted to a pH between 2and 4 with 1N HCl. The solid was collected, and the filtrate wasextracted with methylene chloride and washed and concentrated to giveadditional product. The combined solids were purified by flashchromatography eluting with 100:5:1 methylene chloride:methanol:aceticacid to yield 0.698 g of the title product after removal of the solvent.This material was taken directly to the next step.

Step 253l.8-(3-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A sample of the product from Step 253k above (0.697 g, 1.564 mmol) wasdissolved in 17 mL of anhydrous methylene chloride, 5.0 mL of 4N HCl indioxane was added, and the reaction was stirred for 1.75 hours. Etherwas added, and the precipitate was collected by filtration and washedwith ether. The solid was dissolved in water, filtered through asintered glass funnel, and freeze-dried to give the title product as ayellow solid. mp 230°-232° C. (dec). MS 346 (M-Cl)⁺ ; 1H NMR (DMSO) ∂:0.58(m, 2H), 0.99 (m, 2H), 2.15 (m, 1H), 2.31 (m, 2H), 263 (s, 3H), 3.77(m, 2H), 3.99-4.06 (m, 3H), 7.94 (s, 1H), 8.39 (br s, 3H), 9.10 (d, 1H,=11 Hz), 13.85 (br s); IR 3440, 1695, 1610 cm⁻¹.

EXAMPLE 2548-(3-(aminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-(BOC-amino)pyrrolidine of Step 253j above was replaced by3-BOC-aminomethylpyrrolidine and the reaction product was carriedforward as in Steps 253K and 253l, above, to prepare 0.085 g of thetitle compound. MS 360 (M-Cl)⁺ ; 1H NMR (DMSO) ∂: 0.60 (m, 2H), 0.99 (m,2H), 1.81 (m, 1H), 2.18 (m, 1H), 2.30 (m, 1H), 2.60 (s, 3H) , 2.98 (m,2H), 3.66-3.81 (m, 5H), 7.90 (s, 1H), 8.09 (br s, 3H), 9.06 (d, 1H, J=11Hz), 13.85 (br s, 1H).

EXAMPLE 255 8-(2S,4S-4-amino-2-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by(2S,4S)-4-(BOC-amino)-2-methylpyrrolidine and the reaction product wascarried forward as in Steps 253K and 253l, above, to prepare 0.071 g ofthe title compound. MS 360 (M-Cl)⁺ ; 1H NMR (DMSO) ∂: 0.51 (m, 1H), 0.63(m, 1H), 0.90 (m, 1H), 1.09 (m, 1H), 1.17 (d, 3H, J=6 Hz), 2.01 (m, 1H),2.40 (m, 2H), 2.64 (s, 3H), 3.40 (m, 1H), 3.98 (m, 1H), 4.31 (m, 1H),4.61 (m, 1H), 8.00 (s, 1H), 9.17 (d, 1H, J=11 Hz).

EXAMPLE 2568-(3-aminoazetidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by3-(BOC-amino)azetidine and the reaction product was carried forward asin Steps 253K and 253l, above, to prepare 0.094 g of the title compound.MS 332 (M-Cl)⁺ ; 1H NMR (DMSO) ∂: 0.61 (m, 2H), 1.00 (m, 2H), 2.30 (m,1H), 2.61 (s, 3H), 4.15 (m, 1H), 4.56 (m, 2H), 4.86 (m, 2H), 7.89 (s,1H), 851 (br s, 3H), 9.13 (d, 1H, J=10 Hz).

EXAMPLE 2578-(3(S)-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by3(S)-(BOC-amino)pyrrolidine and the reaction product was carried forwardas in Steps 253K and 253l, above, to prepare 0.087 g of the titlecompound. MS 346 (M-Cl)⁺ ; 1H NMR (DMSO) ∂: 0.59 (m, 2H), 0.99 (m, 2H),2.14 (m, 1H), 2.31 (m, 2H), 2.63 (s, 3H), 3.76 (m, 2H), 398-4.07 (m,3H), 7.94 (s, 1H), 8.36 (br s, 3H), 9.11 (d, 1H, J=11 Hz).

EXAMPLE 258 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-methyl-1-piperazinyl)-4H-quinolizine-3-carboxylic acid hydrochloride

The 3-BOC-arninopyrrolidine of Step 253j above was replaced by2-methylpiperazine (Aldrich Chemical Co.), and the reaction product wascarded forward as in Steps 253K and 253l, above, to prepare 225 mg ofthe title compound. mp>300° C. IR (KBr): 3420, 1720, 1650 cm⁻¹. MS 360(M-Cl)⁺. ¹ H NMR (CD₃ OD) ∂: 0.75 (m, 2H), 1.10 (m, 2H), 1.40 (d, 3H,J=7.5 Hz), 2.90 (s, 3H), 3.45 (m, 3H), 3.71 (m, 4H), 8.23 (s, 1H), 9.40(d, 1H, J=12 Hz). Calc. for C₁₉ H₂₃ ClFN₃ O₃.1.25 H₂ O: C, 54.55; H,6.14; N, 10.04; Found: C, 54.78; H, 5.78; N, 10.05.

EXAMPLE 2591-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-piperazinyl-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by piperazine(Aldrich Chemical Co.), and the reaction product was carried forward asin Steps 253K and 253l, above, to prepare 75 mg of the title compound.mp=279°-280° C. IR (KBr): 3420, 1710, 1650, 1610 cm⁻¹. MS 346 (M-Cl)⁺. ¹H NMR (CD₃ OD) ∂: 0.72 (m, 2H), 2.43 (m, 1H), 2.92 (s, 3H), 3.43 (m,4H), 3.72 (m, 4H), 8.25 (s, 1H), 9.30 (d, 1H, J=12 Hz). Calc. for C₁₈H₂₁ ClFN₃ O₃.1.5 H₂ O: C, 55.32; H, 5.67; N, 10.75; Found: C, 55.52; H,5.49; N, 10.59.

EXAMPLE 260-cyclopropyl-7-fluoro-9-methyl-8-(2-((N-methyl)aminomethyl)-4-morpholinyl)-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Step 260a. 1-N-benzyl-3-(chloromethyl)morpholine

A mixture of 1.5 g (10 mmol) of N-benzyl-ethanolamine (Aldrich ChemicalCo.) and 7.8 mL of epichlorohydrin was heated at 40° C. for 30 min. Thereaction was cooled, and the excess epichlorohydrin was removed with arotary evaporator. The residue was dried under vacuum, dissolved in 30mL of conc. H₂ SO₄, and the mixture heated at 150° C. for 30 min. Thereaction was quenched by pouring onto ice, and the pH was adjusted withNaOH to pH 13. The basic solution was extracted with toulene (3×), andthe extracts were dried over Na₂ SO₄, filtered, and the solvent removeunder vacuum. The residue was dried under vacuum to yield 193 mg of thetitle product.

Step 260b. 1-N-benzyl-3-((N-methylamino)methyl)-morpholine

A thick-walled glass tube was charged with 8.83 g ofN-benzyl-3-(chloromethyl)morpholine, from step 260a above, dissolved in15 mL of methanol. The tube and its contents were cooled and 25 mL ofanhydrous methylamine was added. The tube was sealed and heated at 100°C. for 24 hours. The seal was broken, and the solvent was removed undervaccum. The residue was diluted with 100 mL of 10% Na₂ CO₃, thenextracted 3× with methylene chloride. The extract was dried over Na₂SO₄, filtered, and the solvent was removed on a rotary evaporator toyield 8.6 g of the title product.

Step 260 c. 1-N-benzyl-3-((N-BOC-N-methylamino)methyl)-morpholine

To a dry flask under positive N₂ atmosphere was added 8.6 g (39 mmol) ofthe 1-N-benzyl-3-((N-methylamino)methyl)-morpholine, from step 260babove, in 100 mL of dry methylene chloride. The solution was cooled inan ice bath and 8.6 mL (64.3 mmol) of triethylamine and 12.7 g (58.5mmol) of di-t-butyldicarbonate was added. The reaction mixture wasstirred at 0°-5° C. for 30 min, then warmed to room temperature andstirred for 72 hours. The reaction contents were diluted with 100 mL ofmethylene chloride, which was then washed with water and dried over Na₂SO₄. The solution was filtered, the solvent was removed on a rotaryevaporator, and the residue dried under vacuum to afford 12.4 g of crudetitle product. The product was purified by column chromatography toyield 7.4 g of the title product as a colorless oil. Anal Calc. forC11H22N203: C, 67.47; H, 8.81;,N, 8.74; Found: C, 67.00; H, 8.53; N,8.66.

Step 260d. 2-(N-BOC-N-methyl-aminomethyl)morpholine

A 1.10 g (3.43 mmol sample of1-N-benzyl-3-((N-BOC-N-methylamino)methyl)-morpholine, from step 260cabove, was dissolved in 100 mL of methanol. To this was added 500 mg of20% Pd/C, and the mixture was stirred at room temperature under 4 atm ofH₂ for 16 hours. The catalyst was removed by filtration, the solvent wasremoved with a rotary evaporator, and the residue was dried under vacuumto yield 794 mg of the title product as a colorless oil.

Step 260e.1-cyclopropyl-7-fluoro-9-methyl-8-(2-((N-methyl)aminomethyl)-4-morpholinyl)-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by2-(N-BOC-N-methylaminomethyl)morpholine (from step 260d above)and thereaction product was carried forward as in Steps 253K and 253l, above,to prepare 280 mg of the title compound. mp=208°-210° C. IR (KBr): 3420,1720, 1700, 1650 cm⁻¹. MS 390 (M-Cl)⁺. ¹ H NMR (CD₃ OD) ∂: 0.70 (m, 2H),1.10 (m, 2H), 2.38 (m, 1H), 2.78 (s, 3H), 2.90 (s, 3H), 3.10-3.30 (m,2H), 350-4.15 (m, 7H), 8.12 (s, 1H), 9.20 (d, 1H, J=14 Hz). Calc. forC₂₀ H₂₅ ClFN₃ O₄.2H₂ O: C, 52.01; H, 6.33; N, 9.10; Found: C, 51.90; H,5.92; N, 9.09.

EXAMPLE 2611-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(1,2,3,4-tetrahydro-2-isoquinolinyl)-4H-quinolizine-3-carboxylicacid

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by1,2,3,4-tetrahydroisoquinoline (Aldrich Chemical Co.), and the reactionproduct was carded forward as in Steps 253K and 253l, above, to prepare315 mg of the title compound. mp=214°-215° C. IR (KBr): 3420, 1730, 1680cm⁻¹. MS 393 (M+H)⁺. ¹ H NMR (CDCl₃) ∂: 0.70 (m, 2H), 1.08 (m, 2H), 2.30(m, 1H), 2.85 (s, 3H),3.10 (dd, 2H, J=6 Hz), 3.75 (m, 2H), 4.60 (s, 2H),7.28 (m, 4H), 8.40 (s, 1H), 9.22 (d, 1H, J=12 Hz). Calc. for C₂₃ H₂₁ FN₂O₃.1.25 H₂ O: C, 66.58; H, 5.71; H, 6.75; Found: C, 66.56; H, 5.26; N,6.62.

EXAMPLE 2621-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-1-piperdinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

Step 262a. N-benzyl-4-(N-hydroxyimino)piperidine

A 3.78 g (20 mmol) sample of N-benzyl-4-oxo-piperidine (Aldrich ChemcialCo.) was dissolved in 50 mL of methanol. To this solution was added 4.16g (60 mmol) of hydroxylamine hydrochloride and 5.2 g NaHCO3 (62 mmol)(Dissolved in 80 mL of water and added in 5 mL portions). The mixturewas then stirred at room temperature for 18 hours. The mixture wasfiltered, and the solvent was removed from the filtrate on a rotaryevaporator to give 3.05 g of the title product. mp 127°-128° C.

Step 262b. 1-N-benzyl-4-aminopiperidine

A 2.04 g (9.98 mmol) sample of the oxime from step 262a above wasdissolved in 200 mL of methanol and reduced with 10 g of Raney nickelunder 4 atmosphere of H₂ at room temperature for 4 hours. The catalystwas removed by filtration, and the solvent was removed on a rotaryevaporator. The residue was dried under vacuum to yield 1.79 g of thetitle product. MS M/Z: 191 (M+H)⁺.

Step 262c. 1-N-benzyl-4-BOC-aminopiperidine

In a dry system under N₂ pressure was introduced 1.78 g of the1-N-benzyl-4aminopiperidine, from step 262b above, dissolved in 9 mL ofdry methylene chloride. To this was added 1.6 mL (12 mmol) oftriethylamine and 2.45 g (11.2 mmol) of di-t-butyldicarbonate. Thereaction mixture was stirred at room temperature for 96 hours. Thecontents were diluted with 125 mL of methylene chloride and washed withwater. The organic layer was dried over Na₂ SO₄, filtered, and thesolvent removed on a rotary evaporator. The residue was dried undervacuum to yield 2.45 g of the title product as an off-white solid. Thecrude product was purified by column chromatography on silica gel,eluting with 2% methanol in methylene chloride. Removal of the solventgave 1.74 g of product, which was the recrystallized from ethanol, anddried under vacuum. mp. 121°-122° C. Anal. calc. for C17H25N202: C,70.31; H, 9.02; N, 9.65; Found: C, 70.26; H, 9.02; N, 9.55.

Step 262d. 4-BOC-aminopiperidine

The benzyl group was removed from the product of step 262c by theprocedure described for Example 260d above, to afford the title product.

Step 262e.1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-1-piperdinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by4-(BOC-amino)methylpiperidine, from step 262d above, and the reactionproduct was carried forward as in Steps 253K and 253l, above, to prepare480 mg of the title compound. mp=231°-232° C. IR (KBr): 3420, 1700, 1610cm⁻¹. MS 360 (M-Cl)⁺. ¹ H NMR (CD₃ OD) ∂: 0.70 (m, 2H), 1.08 (m, 2H),1.85 (m, 1H), 2.10 (m, 1H), 2.18 (m, 2H), 2.35 (m, 2H), 2.87 (s, 3H),3.50 (m, 2H), 3.70 (m, 1H), 8.16 (s, 1H), 9.22 (d, 2H, J=9 Hz). Calc.for C₁₉ H₂₃ ClFN₃ O₃.0.75 H₂ O: C, 55.75; H, 6.03; H, 10.26; Found: C,55.70; H, 6.07; N, 10.36.

EXAMPLE 2631-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino-1-piperdinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by3-amino-piperidine hydrochloride (Aldrich Chemical Co.), which wasneutralized with triethylamine, and the reaction product was carriedforward as in Steps 253K and 253l, above, to prepare 250 mg of the titlecompound. mp=222°-223° C. IR (KBr): 3400, 1700, 1680 cm⁻¹. MS 360(M-Cl)⁺. ¹ H NMR (CD₃ OD) ∂: 0.70 (m, 2H, J=6 Hz), 1.10 (m, 2H, J=6 Hz),1.70 (m,2H), 2.05 (m, 3H), 2.30 (m, 2H), 2.40 (m, 2H), 2.87 (s, 3H),3.90 (m, 1H), 8.18 (s, 1H), 9.20 (d, 1H, J=9 Hz). Calc for C₁₉ H₂₃ ClFN₃O₃.2 H₂ O: C, 52.84; H, 6.30; H, 9.73; Found: C, 52.62; H, 6.62; N,9.36.

EXAMPLE 264 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)-1-piperdinyl)-4H-quinolizine-3-carboxylic acid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by4(aminomethyl)piperidine (Aldrich Chemical Co.), and the reactionproduct was carried forward as in Steps 253K and 253l, above, to prepare157 mg of the title compound. mp>300° C. IR (KBr): 3410, 1720, 1660cm⁻¹. MS 374 (M-Cl)⁺. ¹ H NMR (CD₃ OD) ∂: 0.70 (m, 2H), 1.08 (m, 2H),1.55 (m, 1H), 1.95 (m, 2H), 2.42 (m, 2H), 2.83 (s, 3H), 2.95 (m, 3H),3.40 (m, 2H), 3.60 (m, 2H), 8.18 (s, 1H), 9.22 (d, 1H, J=9 Hz). Calc.for C₂₀ H₂₅ ClFN₃ O₃ ·1.75 H₂ O: C, 54.42; H, 6.51; H, 9.52; Found: C,53.92; H, 6.85; N, 9.73.

EXAMPLE 2651-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(5-amino-1,2,3,4-tetrahydro-2-isoquinolinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

Step 265a. 5-amino- 1,2,3,4-tetrahydroisoquinoline

A 1.0 g (0.69 mmol) sample of 5-aminoisoquinoline (Aldrich Chemical Co.)was dissolved in 100 mL of methanol and reduced with 250 mg PtO₂catalyst at 25° C. under 4 atmospheres of H₂ for 8 hours. The catalystwas removed by filtration, the solvent was removed on a rotaryevaporator, and the residue was dried under vacuum to give 1.01 g ofcrude product. The material was crystallized from i-propanol and driedunder vacuum, yield 602 mg. mp=153°-154° C. MS M/Z: 149 (M+H)⁺, 166(M+NH₄)⁺.

Step 265b.1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(5-amino-1,2,3,4-tetrahydro-2-isoquinolinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by5-amino-1,2,3,4-tetrahydroisoquinoline, prepared in step 265a above, andthe reaction product was carried forward as in Steps 253K and 253l,above, to prepare 507 mg of the title compound. mp=185°-187° C. IR(KBr): 3380, 1710, 1650 cm⁻¹. MS 408 (M-Cl)⁺, 390 (M+NH₄ -Cl)⁺. ¹ H NMR(CD₃ OD) ∂: 0.72 (m, 2H, J=6, J=3 Hz), 1.10 (m, 2H, J=3 Hz), 2.40 (m,1H), 2.90 (s, 3H), 3.07 (dd, 2H, J=7.5 Hz), 3.90 (dd, 2H, J=7.5, J=3Hz), 4.74 (s 2H), 7.28 (m, 2H), 7.35 (m, 1H, J=9 Hz), 8.17 (s, 1H), 9.25(d, 1H, J=12 Hz). Calc. for C₂₃ H₂₃ ClFN₃ O₃.0.75 H₂ O: C, 60.39; H,5.40; H, 9.19; Found: C, 60.38; H, 5.16; N, 9.10.

EXAMPLE 2661-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(1-pyrrolyl)-1-piperidinyl)-4H-quinolizine-3-carboxylicacid

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by4-(1-pyrrrolyl)piperidine (prepared from N-benzyl-4-hydroxypiperidine bymesylation followed by displacing the mesyl group with pyrrole andremoving the benzyl group), and the reaction product was carried forwardas in Steps 253K and 253l, above, to prepare 386 mg of the titlecompound. mp=268°-269° C. IR (KBr): 3420, 1720, 1660 cm⁻¹. MS 427(M+NH₄)⁺, 410 (M+H)⁺. ¹ H NMR (CD₃ OD) ∂: 0.70 (m, 2H), 1.03 (m, 2H),2.14 (m, 4H), 2.40 (m, 1H), 2.90 (s, 3H), 3.60 (m, 4H), 4.18 (m, 1H),6.08 (dd, 2H, J=3 Hz), 6.84 (dd, 2H, J=3 Hz), 8.37 (s, 1H), 9.25 (d, 1H,J=12 Hz). Calc. for C₂₃ H₂₄ FN₃ O₃.1.25 H₂ O: C, 63.95; H, 6.18; H,9.73; Found: C, 63.60; H, 6.61; N, 9.43.

EXAMPLE 2671-cyclopropyl-8-(cis-3,5-dimethyl-1-piperazinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced bycis-3,5dimethylpiperazine (Aldrich Chemical Co.) and the reactionproduct was carried forward as in Steps 253j and 253k, above, to prepare0.46 g of the title compound. IR (KBr): 3450, 1720, 1650, 1610 cm⁻¹. MS374 (M-Cl)⁺. ¹ H NMR (D₆ DMSO) ∂: 0.70 (m, 2H), 1.04 (m, 2H), 1.30 (d,6H, J=7 Hz), 2.41 (m, 1H), 2.80 (s, 3H), 3.40-3.65 (m, 6H), 8.03 (s,1H), 9.26 (d, 1H, J=9Hz), 9.60 (br s, 1H). Calc. for C₂₀ H₂₅ ClFN₃O₃.0.75 H₂ O: C, 56.74; H,6.31; N, 9.92; Found: C, 56.66; H, 6.21; N,9.74.

EXAMPLE 2681-cyclopropyl-8-(2,7-diazabicyclo[3.3.0]oct-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by7-BOC-2,7-diaza[3.3.0]octane (prepared according to U.S. Pat. No.5,071,999) and the reaction product was carried forward as in Steps253j, k, and l, above, to prepare 0.34 g of the title compound. IR(KBr): 3400, 1700, 1650, 1605 cm⁻¹. MS 372 (M-Cl)⁺. ¹ H NMR (D₆ DMSO) ∂:0.60 (m, 2H), 0.91 (m, 1H), 2.03-2.10 (m, 3H), 2.36 (m, 1H), 2.68 (s,3H), 3.19 (m, 1H), 3.49 (m, 2H), 4.15 (m, 1H), 5.50 (m, 1H), 7.98 (s,1H), 9.14 (d, 1H, J=10 Hz), 9.40 (br s, 1H). Calc. for C₂₀ H₂₄ Cl₂ FN₃O₃ : C, 54.06; H, 5.44; N, 9.46; Found: C, 53.86; H, 5.48; N, 9.63.

EXAMPLE 2691-cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by8-BOC-2,8-diaza[4.3.0]nonane (prepared according to U.S. Pat. No.5,059,597), and the reaction product was carried forward as in Steps253K and 253l, above, to prepare 0.50 g of the title compound. IR (KBr):3400, 1690, 1650, 1600 cm⁻¹. MS 386 (M-Cl)⁺. ¹ H NMR (D₆ DMSO) ∂:0.56(m, 1H), 0.62 (m, 1H), 0.93 (m, 1H), 1.07 (m, 1H), 1.60-1.80 (m, 4H),2.28-2.32 (m, 2H), 2.67 (s, 3H), 2.72 (m, 1H), 2.94 (m, 1H), 3.70 (m,2H), 3.91 (m, 1H), 4.03 (m, 1H), 4.35 (m, 1H), 7.93 (s, 1H), 8.90 (br s,1H), 9.10 (d, 1H, J=11 Hz), 9.48 (br s, 1H), 13.85 (br s, 1h). Calc. forC₂₁ H₂₆ Cl₂ FN₃ O₃ : C, 55.03; H, 5.72; N, 9.17; Found: C, 54.75; H,5.82; N, 9.38.

EXAMPLE 2701-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-(1-pyrrolyl)-1-pyrrolidinyl)-4H-quinolizine-3-carboxylicacid

A mixture of 25 mg8-(3(S)-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride (from Example 257) and 40 mg of sodium acetate in 0.7mL of ethyl acetate was heated to 100° C. To this solution was added0.009 mL of dimethoxytetrahydrofuran dropwise, and the reaction wasstirred at 110° C. for 5 rnin, then quenched by addition of water. Themixture was extracted twice with methylene chloride, and the extract waswashed with water, dried over MgSO₄ and concentrated. The residue waspurified by preparative TLC, eluting with 100:10 chloroform:methanol, togive 13.6 mg of the title product as a yellow solid after removal of thesolvent. MS 395 (M-Cl)⁺. ¹ H NMR (CDCl₃) ∂: 0.67 (m, 2H), 1.00 (m, 2H),2.20 (m, 1H), 2.46 (m, 1H), 2.56 (m, 1H), 2.66 (s, 3H), 3.89 (m, 1H),3.99 (m, 2H0, 4.15 (m, 1H), 4.86 (m, 1H), 6.23 (t, 2H, J=2 Hz), 6.79 (t,2H, J=2 hz), 8.32 (s, 1H), 9.15 (d, 1H, J=10 Hz), 13.83 (br, 1H).

EXAMPLE 2711-cyclopropyl-7-fluoro-8-(3-hydroxy-1-pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by3-hydroxypyrrolidine (Aldrich Chemical Co.), and the reaction productwas carried forward as in Steps 253j and 253k above, to prepare 0.15 gof the title compound. IR (KBr): 3425, 1690, 1650, 1600 cm⁻¹. MS 346(M+H)⁺. ¹ H NMR (DMSO-d₆) ∂: 0.59 (m, 2H), 0.93 (m, 1H), 1.03 (m, 1H),196-201 (m, 3H), 2.29 (m, 1H), 2.49 (s, 3H), 3.43 (m, 1H), 3.69 (m, 1H),4.01 (m, 2H), 4.42 (m, 1H), 5.15 (d, 1H, J=3 Hz), 7.89 (s, 1H), 9.05 (d,1H, J=11 Hz), 13.86 (br s, 1H). Calc. for C₁₈ H₁₉ FN₂ O₄ : C, 62.42; H,5.53; N, 8.09; Found: C, 62.20; H, 5.55; N, 8.09.

EXAMPLE 2721-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

The 3-BOC-aminopyrrolidine of Step 253j above was replaced by1-methylpiperazine (Aldrich Chemical Co.), and the reaction product wascarried forward as in Steps 253j and 253k, above, to prepare 0.15 g ofthe title compound. mp=210°-216° C. (dec). MS 360 (M-Cl)⁺. ¹ H NMR(CDCl₃) ∂: 0.70 (m, 2H), 1.02 (m, 2H), 2.28 (m, 1H), 2.40 (s, 3H), 2.60(m, 4H), 2.79 (s, 3H), 3.48 (m, 4H), 8.37 (s, 1H), 9.21 (d, 1H, J=9 Hz).

EXAMPLE 2731-cyclopropyl-9-chloro-7-fluoro-8-(3-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid trifluoroacetic acid salt

The 4-t-butoxy-2,3,6-trifluoro-5-methylpyridine of Step 253d above wasreplaced by 4-t-butoxy-3-chloro-2,5,6-trifluoropyridine (from step 253aabove), and the methanol solvent was replace by benzene, and thereaction product was carried forward as in Steps 253d-l above, and the4N HCl in dioxane of Step 253l was replaced with trifluoroacetic acid.to prepare 0.13 g of the title compound. MS 366 (M-CF₃ CO₂)⁺. ¹ H NMR(D₆ -DMSO) ∂: 0.58 (m, 2H), 0.97 (m, 2H), 2.11 (m, 1H), 2.31 (m, 1H),2.44 (m, 1H), 3.83 (m, 1H), 3.97 (m, 2H), 4.10 (m, 1H), 4.20 (m, 1H),8.09 (s, 1H), 8.09 (br, 3H), 9.18 (d, 1H, J=11 Hz). Calc. for C₁₇ H₁₇ClFN₃ O₃ :.CF₃ COOH.0.5 H₂ O: C, 46.69; H, 3.92; N, 8.60; Found: C,46.62; H, 3.64; N, 8.45.

EXAMPLE 2748-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Step 274a. 4-t-butoxy-2,3,5,6-tetrafluoropyridine

A 158.5 g (0.938 mmol) sample of pentafluoropyridine (Aldrich ChemicalCo.) was dissolved in 600 mL of THF and cooled to -78° C. To this wasadded 88.29 g (0.919 mmol) of sodium-t-butoxide in 800 mL of THF over a30 min period, with stirring and while maintaining the temperature at-78° C. The mixture was stirred for another 30 min at this temperature,then the temperature of the bath was raised to -20° C., and the reactionwas stirred at this temperature for 64 hours. The reaction mixture wasremoved from the cold bath and diluted with 1.5 L of ether, thenfiltered through a diatomaceous earth filter aid. The solvent wasremoved under vacuum to leave a yellow oil. The oil was purified byvacuum distillation to afford 141.34 g of the title product.

Step274b. 4-t-butoxy-2,3,5-trifluoropyridine

A 20.0 g (0.089 mmol) sample of the product from step 274a above wasdissolved in 100 mL of absolute ethanol, and 26.08 mL (0.538 mol) ofhydrazine monohydrate was added. The reaction was stirred for 1 hour atroom temperature and 1 hour at reflux. The solvent was removed undervacuum. The residue was dissolved in ether and washed with water andbrine. The organic phase was dried over MgSO₄, and the solvent wasremoved under vacuum to yield a yellow solid. This material wasdissolved in 120 mL of toluene, 60 mL of 20% sodium hydroxide was added,and air was bubbled through the stirred solution for 18 hours. To thereaction was added 100 mL of ether, and the organic phase was separated,washed with water and brine, and dried over MgSO₄. Removal of thesolvent, and purification of the residue with flash chromatography onsilica gel, eluting with 1:16 ethyl acetate:hexane, gave 14.6 g of thetitle product as a reddish liquid.

Step 274c.8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Replacing the 4-t-butoxy-2,5-difiuoro-3-methylpyridine of step 253e withthe 4-t-butoxy-2,3,5-trifluoropyridine from step 274b above, andcarrying the product forward according to the procedures of Steps253e-l, 76 mg of the title compound was prepared. MS M/Z: 350 (M-Cl)⁺. ¹H NMR (D₆ -DMSO) ∂: 0.65 (m, 2H), 0.90 (m, 2H), 2.15-2.30 (m, 3H,3.95-4.00 (m, 3H), 4.18 (m, 2H), 7.81 (s, 1H), 8.46 (br, 3H), 9.17 (d,1H, J=9 Hz).

EXAMPLE 2758-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Step 275a. 4-t-butoxy-2,3,6-trifluoro-5-hydroxypyridine

A 11.16 g (54.39 mmol) sample of 4-t-butoxy-2,3,6-trifluoropyridine,from Example 253 step b above, was dissoved in 50 mL of THF, and thesolution was cooled to -78° C. To this solution was added LDA (65.6mmol) with stirring for 30 min, during which a solid preciptated. Tothis mixture was added 7.5 mL of trimethoxyborane, with stirring for 25min at -78° C. To this mixture was added 10 mL of acetic acid, and themixture was stirred and allowed to warm to room temperature. Next wasadded 100 mL of 30% hydrogen peroxide and 100 mL of 2N sodium hydroxidewhile cooling in an ice bath. The mixture was then stirred at roomtemperature for 16 hours, and quenched with saturated NH₄ Cl solution.The mixture was extracted with ether, and the extract was washed withbrine and dried over MgSO₄. The solvent was removed under vacuum, andthe residue was purified by flash chromatography on silica gel, elutingwith 1:8 ethyl acetate:hexane. Removal of the solvent gave 9.769 g ofthe title product as a colorless liquid.

Step 275b. 4-t-butoxy-2,3,6-trifluoro-5-methoxypyridine

To a solution of 237 mg (1.07 mmol) of4-t-butoxy-2,3,6-trifluoro-5-hydroxypyridine, from step 275a above, in 3mL of anhydrous THF was added 335 mg (1.277 mmol)of triphenyl phosphineand 0.060 mL (1.48 mmol) of methanol. To this solution was added 0.200mL (1.270 mmol) of DEAD dropwise at room temperature. The reaction wascomplete in 10 min, so the solvents were removed under vacuum and theresidue was purified by flash chromatography on silica gel, eluting with1:16 ethyl acetate:hexane to give 215.6 mg of the title product as acolorless liquid after removal of the solvent.

Step 275c.8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Replacing the 4-t-butoxy-2,3,6-trifluoro-5-methylpyridine of Example 253step c with the 4-t-butoxy-2,3,6-trifluoro-5-methoxypyridine of step275b above and carrying the product forward according to the proceduresof Steps 253d-l, 120 mg of the title compound was prepared. MS M/Z: 362(M-Cl)⁺. IR (KBr): 3440, 1799, 1650, 1610 cm⁻¹. ¹ H NMR (D₆ -DMSO) ∂:0.62 (m, 2H), 0.91 (m, 2H), 2.12 (m, 1H), 2.29 (m, 1H), 2.39 (m, 1H),3.62 (s, 3H), 3.81 (m, 1H), 3.94 (m, 2H), 4.06 (m, 2H), 7.79 (s, 1H),8.30 (br, 3H), 9.13 (d, 1H, J=10 Hz), 13.79 (br, 1H). Calc. for C₁₈ H₂₀FN₃ O₄.2HCl.0.5H₂ O: C, 48.77; H, 5.23; N, 9.48; Found: C, 48.65; H,5.19; N, 9.56.

EXAMPLE 2761-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Step 276a. 1-N-benzyl-3(S)-(BOC-amino)-pyrrolidine

A 4.2 g sample of (3S)-3-BOC-aminopyrrolidine (TCI America) and 4.7 mLof triethylamine were dissolved in 75 mL of methylene chloride at roomtemperature. To this solution was added 2.95 mL of benzyl bromidedropwise, and the reaction was heated at reflux for 6 hours. Aftercooling, the solution was washed with water, and the solvent was driedand evaporated to give 5.10 g of the title product as a white solid.

Step 276b. 1-N-benzyl-3(S)-(methylamino)-pyrrolidine

The 5.10 g sample of 1-N-benzyl-3(S)-(BOC-amino)-pyrrolidine, from step276a above, was dissolved in 25 mL of THF, and 55.6g of LiAlH4 (1.0M inTHF) was added. The mixture was stirred and heated at reflux for 4hours. The reaction was quenched with water, and the mixture wasextracted with methylene chloride. The solvent was washed with water,dried over MgSO₄, and removed on a rotary evaporator to yield 2.43 g ofthe title product.

Step 276c. 1-N-benzyl-3(S)-(N-BOC-N-methylamino)-pyrrolidine

A 2.43 g sample of 1-N-benzyl-3(S)-(methylamino)-pyrrolidine, from step276b above, was dissolved in 100 mL of a 4:1 methanol:water mixture, and3.34 g of di-t-butyl dicarbonate was added in portions. The reaction wasstirred at room temperature for 6 hours. The methanol was removed undervacuum, and the aqueous residue was extracted with methylene chloride.The solvent was washed with water, dried over MgSO₄ and removed undervacuum. The residue was purified by chromatography over silica gel,eluting wtih 100:5:0.5 methylene chloride:methanol:NH₄ OH to give 3.23 gof the title product.

Step 276d. 3(S)-(N-BOC-N-methylamino)-pyrrolidine

The product from step 276c was treated according to the procedure ofExample 171 step 5 to remove the benzy protecting group and afford 2.24g of the title product as a white solid.

Step 276e.1-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine of that example with the3(S)-(N-BOC-N-methylamino)-pyrrolidine from step 276d above, andcarrying the reaction product forward according to the procedures ofExample 253 steps k and l, a 452 mg sample of the title product wasobtained. MS: 360 (M-Cl)⁺. IR (KBr): 3450, 1710, 1650, 1610 cm⁻¹. ¹ HNMR (d6-DMSO): 0.62 (m, 2H), 1.00 (m, 2H), 2.26 (m, 1H), 2.33 (m, 3H),2.65 (s, 6H), 3.75 (m, 1H), 3.90 (m, 2H), 4.05 (m, 2H), 7.94 (s, 1H),9.12 1H, J=10 Hz), 9.18 (br s, 2H), 13.86 (br s, 1H). Anal. Calc. forC₁₉ H₂₂ FN₃ O₃.HCl.H₂ O: C, 55.14; H, 6.09; N, 10.15; Found: C, 55.29;H, 5.99; N, 10.18.

EXAMPLE 2771-cyclopropyl-7-fluoro-9-methyl-8-(3(R)-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Step 277a. 1-N-benzyl-3(R)-(BOC-amino)-pyrrolidine

Following the procedure of Example 276 step a, replacing the(3S)-3-BOC-aminopyrrolidine of step 276a with(3R)-3-BOC-aminopyrrolidine (TCI America), the title compound wasprepared.

Step 277b. 3(R)-(BOC-amino)pyrrolidine

The benzyl group was removed from the product of step 277a by theprocedure of step 276d above, to give the title product.

Step 277c.1-cyclopropyl-7-fluoro-9-methyl-8-(3(R)-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-(BOC-amino)pyrrolidine of that example with the3(R)-(BOC-amino)-pyrrolidine from step 277b above, and carrying thereaction product forward according to the procedures of Example 253steps k and l, a 452 mg sample of the title product was obtained. MS:346 (M-Cl)⁺. IR (KBr): 3440, 1700, 1650, 1610 cm⁻¹. ¹ H NMR (d6-DMSO):0.59 (m, 2H), 1.00 (m, 2H), 2.15 (m, 1H), 2.31 (m, 2H), 2.63 (s, 3H),3.76 (m, 2H), 4.00-4.07 (m, 3H), 8.40 (br, 3H), 9.10 (d, 1H, J=11 Hz)C₁₈ H₂₀ FN₃ O₃.HCl.H₂ O: C, 54.07; H, 5.80; N, 10.51; Found: C, 54.19;H, 5.65; N, 10.37.

EXAMPLE 278(3R)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2,3,4-ij]quinolizine-5-carboxylicacid hydrochloride

Step 278a. (S)-1-bromo-2-methyl-3-(t-butyldimethylsilyloxy)propane

To a 9.59 g (62.67 mmol) sample of (S)-(+)-3-bromo-2-methyl-1-propanol(Aldrich Chemical Co.) in 40 mL of DMF was added 4.27 g (62.720 mmol) ofimidazole, and the solution was cooled to 0° C. To this cooled solutionwas added 9.45 g (62.69 mmol) of t-butyldimethylsilyl chloride, and thesolution was stirred at room temperature for 16 hours. The reactionsolution was poured into water, which was extracted with hexane. Theorganic layer was washed with water, satd. brine, dried over MgSO₄, andconcentrated. The residue was distilled in a kugelrohr apparatus (0.2 mmHg, 50° C.) to yield 15.00 g of the title product as a colorless liquid.

Step 278b. (S)-1-iodo-2-methyl-3 -(t-butyldimethylsilyloxy)propane

A 15.00 g sample of the product from the preceeding step was dissolvedin 100 mL of acetone, and 42.00 g (5 eq) of NaI was added. This mixturewas heated at reflux under N₂ for 9 hours. The mixture was cooled,filtered, and the filtrate was concentrated. The residue was dissolvedin hexane, and the solution was again filtered and concentrated to yield16.62 g of a colorless liquid. This material was distilled in akugelrohr apparatus (0.2 mm Hg, 60° C.) to give 16.479 g of the titleproduct as a colorless liquid. MS: 315 (M+H)⁺. 1H NMR (CDCl₃) ∂: 0.07(s, 6H), 0.90 (s, 9H, 0.95 (d, 3H, J=7 Hz), 1.65 (m, 1H), 3.29 (m, 2H),3.40 (m, 1H), 3.54 (m, 1H).

Step 278c. 1-(2,3,5,6-tetrafluoro-4-pyridyl)-4-methylpiperazine

A 25.10 g sample (0.148 mmol) of pentafluoropyridine (Aldrich ChemicalCo.) and 23.0 mL (0.165 mmol) of triethylamine were dissolved in 150 mLof HPLC grade methylene chloride. To this solution 17.3 mL (0.156 mmol)of N-methylpiperazine were added slowly dropwise at 0° C. The solutionwas stirred for 16 hours at 0° C., then washed with water, dried overMgSO₄ and concentrated to give 36.95 g of the title product as acolorless oil, which solidifed upon standing. MS: 250 (M+H)⁺. ¹ H NMR(CDCl₃) ∂: 2.36 (s, 3H), 2/53 (m, 4H), 3.52 (m, 4H).

Step 278d.(R)-2-methyl-3-(4-(4-methylpiperazinyl)-3.5.6-trifluoro-2-pyvridinyl)-1-propanol

A 5.03 g (16.00 mmol) sample of(S)-1-iodo-2-methyl-3-(t-butyldimethylsilyloxy)propane, from step 278babove, was dissolved in 32 mL of ether and cooled to -78° C. To thissolution was added 19.8 mL (33.66 mmol) of t-buthyllithium (1.7M inpentane), and the temperature was maintained at -78° C. while stirringfor 40 min. The temperature was raised to 0° C., and stirring wascontinued for 30 min. This solution was designated the "lithiumcompound" and was utilized below. In a separate flask 3.99 g (16.01mmol) of 1-(2,3,5,6-tetrafluoro-4-pyddyl)-4-methylpiperazine, from step278c above, was dissolved in 50 mL of THF. To the latter solution at-78° C. was added via cannula the solution of the lithium compound. Thereaction was stirred at -78° C. for 5 min and at room temperature for 30min. The reaction was quenched by addition of satd. NH₄ Cl, andextracted with ether. The extract was washed with satd. brine, driedover MgSO₄, and concentrated. The residue was dissolved in 30 mL of THF,and 16.5 mL of tetrabutlyammonium fluoride (1N in THF) was added. Themixture was stirred for 16 hours and concentrated. The residue wasslurried with water and extracted with methylene chloride. The organicphase was washed with water, dried over MgSO₄, and concentrated. Theresidue was purified by flash chromatography on silica gel, eluting with100:5:0.5 methylene chloride:methanol:NH₄ OH to give 4.037 g of thetitle product as a colorless viscous oil. MS: 304 (M+H)⁺. ¹ H NMR(CDCl₃) ∂: 0.95 (d, 3H, J=6.6 Hz), 2.11 (m, 1H), 2.35 (s, 3H), 2.53 (m,4H), 2.63 (m, 1H), 2.71 (m, 1H), 3.37-3.50 (m, 6H). Anal calc for C₁₄H₂₀ F₃ N₃ O: C, 55.44; H, 6.65; N, 13.72; Found: C, 55.10; H, 6.24; N,13.72 [α]_(D) =+7.80° (26°, c=1.68, methylene chloride).

Step 278e.(R)-2-methyl-3-(4-(4-methylpiperazinyl)-3,5,-difluoro-2-pyridinyl)-1-propanol

A 4.349 g (14.337 mmol) sample of2-methyl-3-(4-(4-methylpiperazinyl)-3,5,6-trifluoro-2-pyridinyl)-1-propanol,from step 278d above, was dissolved in 20 mL of n-propanol, 3.50 mL(72.15 mmol) of hydrazine hydrate was added, and the reaction was heatedat reflux under N₂ for 17 hours. Another 1.5 mL of hydrazine hydrate wasadded, and the reflux was continued for 15 hours. The solution wasconcentrated on a rotary evaporator, and the residue was slurried inwater, then extracted with methylene chloride. The solvent was washedwith water, dried over MgSO₄, and concentrated to give 4.60 g of thetitle product as a viscous oil. This intermediate hydrazino compound wasdissolved in 300 mL of water, and a solution of 29.78 g of CuSO4 in 400mL of water was added by pipet over a 15 min period. The reaction wasthen heated at reflux under N₂ for 50 min. The reaction was cooled toambient temperature and the solution was made basic with NH₄ OH. Thesolution was extracted with methylene chloride, which was washed withwater, dried over MgSO₄ and concentrated. The residue was purified byflash chromatography on silica gel, eluting with 100:5:0:5 methylenechloride:methanol:NH₄ OH, to give 3.605 g title product. MS: 286 (M+H)⁺.¹ H NMR (CDCl₃) ∂: 0.96 (d, 3H, J=6.6 Hz), 2.14 (m, 1H), 2.35 (s, 3H),2.52 (m, 4H), 2.80 (m, 2H), 3.35-3.41 (m, 5H), 3.51 (m, 1H), 8.01 (d,1H, J=3.3 Hz). Anal. calc. for C₁₄ H₂₁ F₂ N₃ O: C, 58.93; H, 7.42; N,14.73; Found: C, 58.59; H, 7.22; N, 14.31.

Step 278f.3(R)-7-fluoro-3-methyl-8-(4-methyl-1-piperazinyl-2,3-dihydro-4H-pyranol[3,2-b]pyridine

A 3.557 g (12.465 mmol) sample of2-methyl-3-(4-(4-methylpiperazinyl)-3,5,-difluoro-2-pyridinyl)-1-propanol,from step 278e above, was dissolved in 30 mL of dioxane and added to adispersion of 1.12 g (37.33 mmol) of NnH (50% dispersion) in 100 mL ofdioxane. The mixture was heated at reflux for 19 hours, thenconcentrated to dryness. The residue was slurried with water, andextracted with ether. The extract was washed with satd. brine, driedover MgSO₄, and concentrated. The residue was purified by flashchromatography on silica gel, eluting with 100:5:0:5 methylenechloride:methanol:NH₄ OH, to afford 2.299 g of the title product. MS:266 (M+H)⁺. ¹ H NMR (CDCl₃) ∂: 1.07 (d, 3H, J=6.6 Hz), 2.21 (m, 1H),2.38 (s, 3H), 2.49 (m, 1H), 2.57 (m, 4H), 2.94 (m, 1H), 3.37 (m, 4H),3.67 (dd, 1H, J=9.6, 10.3 Hz), 4.23 (m, 1H), 7.90 (d, 1H, J=3.3 Hz).Anal calc. for C₁₄ H₂₀ FN₃ O: C, 63.38; H, 7.60; N, 15.84; Found: C,63.58; H, 7.60; N, 15.84.

Step 278g.3(R)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyranol[2,3,4-ij]quinolizine-5-carboxylicacid, ethyl ester

A 132.7 mg (0.500 mmol) sample of3(R)-7-fluoro-3-methyl-8-(4-methyl-1-piperazinyl)2,3-dihydro-4H-pyrano[3,2-b]pyridine,from step 278f above, was dissolved in 5 mL of THF and cooled to -78° C.To this solution was added 0.22 mL of n-butyl lithium (0.55 mmol, 2.5Min hexane), and the reaction was stirred at -78° C. for 30 min. To thereaction vessel was added 0.120 mL (0.594 mmol) of diethoxyethoxymethylenemalonate, and the reaction was stirred for 5 min at -78°C. and at room temperature for 15 min. The solvent was removed, and theresidue was dissolved in ethanol. To this was added 1.0 mL of piperidineand 0.2 mL of acetic acid, and the solution was heated at reflux for 16hours. The solvents were removed, and the residue was dissolved inmethylene chloride. This solution was washed with water, dried overMgSO₄, and concentrated. The residue was triturated with 50:50ether:hexane, and the solid was isolated, and the filtrate purified bychromatography on silica gel, eluting with 100:5:0:5 methylenechloride:methanol:NH₄ OH, to afford a total of 88.9 mg of the titleproduct. MS: 390 (M+H)⁺. IR 3440, 1710, 1630 cm⁻¹. ¹ H NMR (CDCl₃) ∂:1.34 (d, 3H, J=7 Hz), 1.42 (t, 3H, J=7 hz), 2.37 (s, 3H), 2.56 (m, 4H),3.12 (m, 1H), 3.55 (m, 4H), 4.02 (dd, 1H, J=11, 6 Hz), 4.28 (dd, 1H,J=11, 4 Hz), 4.41 (q, 2H, J=7 Hz), 8.03 (s, 1H), 9.06 (d, 1H, J=9 Hz).Anal calc. for C₂₀ H₂₄ FN₃ O₄ : C, 61.69; H, 6.21; N, 10.79; Found: C,61.42; H, 5.89; N, 10.65. [α]_(D) =-37.14° (25° C., c=0.28, methylenechloride).

Step 278h.3(R)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2,3,4-ij]quinolizine-5-carboxylicacid

A 657 mg(1.687 mmol) sample of3(R)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid, ethyl ester, from step 278g above, was dissolved in 6 mL of THFand 142 mg of LiOH.H₂ O and 3 mL of water were added. The mixture washeated at 60° C. under N₂ for 80 min. The solvent was removed underreduced pressure, and the aqueous residue was diluted with additionalwater and extracted with methylene chloride. The aqueous solution wasthen neuralized to ph& with 10% HCl, and extracted with methylenechloride. The extract was washed with water, dried over MgSO₄ andconcentrated to dryness. The residue was dissolved in methylenechloride, which was then filtered through a sintered glass funnel. Thefiltrate was concentrated to dryness, and the residue was trituratedwith 1:1 ether:hexane to give 494.2 mg of the title product as a yellowsolid after drying. MS: 362 (M+1)⁺. IR 3440, 1720, 1640, 1610 cm₋₁. ¹ HNMR (CDCl₃) ∂: 1.37 (d, 3H, J=7 Hz), 2.39 (s, 3H), 2.60 (m, 4H), 3.19(m, 1H), 3.61 (m, 4H), 4.06 (dd, 1H, J=6.3, 10.6 Hz), 4.34 (dd, 1H,J=3.6, 10.6 Hz), 8.15 (s, 1H), 8.94 (d, 1H, J=8.8 Hz), 13.86 (br, 1H).Anal calc. for C₁₈ H₂₀ FN₃ O₄.0.5H₂ O: C, 59.09; H, 5.65; N, 11.48;Found: C, 59.25; H, 5.59; N, 1139.

Step 278i. 3(R)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid hydrochloride

A 200 mg sample of the free base from the previous step was dissolved in15 mL of methylene chloride, and 0.75 mL of 1M HCl in ether was added.Additional ether was added to precipitate the product, which wascollected by filtration. The solid was dissolved in water, and thesolution was filtered through sintered glass. The filtrate wasfreeze-dried to give 213.1 mg of the title product as a yellow solid.MS: 362 (M-Cl)⁺. IR 3440, 1700, 1637, 1603 cm₋₁. ¹ H NMR (DMSO-d₆) ∂:1.29 (d, 3H, j=7 Hz), 2.76 (s, 3H), 3.15-3.36 (m, 5H), 3.74 (m, 4H),4.18 (dd, 1H, J=5.7, 10.7 Hz), 4.38 (dd, 1H, J=3.7, 10.7 Hz), 8.03 (s,1H), 9.02 (d, 1H), J=8.8 Hz). Anal calc. for C₁₈ H₂₀ FN₃ O₄.HCl.H₂ O: C,51.99; H, 5.57; N, 10.08; Found: C, 51.91; H, 5.33; N, 10.03. [α]_(D)=24.2° (24° C., 0.33, methanol).

EXAMPLE 2793(S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2,3,4-ij]quinolizine-5-carboxylicacid hydrochloride

Step 279a. 2(R)-3-(t-butyldimethylsilyl)oxy-2-methyl-1-propanol

A 24.39 g (265 mmol) sample of (R)-(-)-methyl3-hydroxy-2-methylpropionate (Aldrich Chemical Co.) and 15.46 g (227mmol) of imidazole were dissolved in 120 mL of DMF. The solution wasstirred at 0° C. under N₂ and 34.23 g (227 mmol) of t-butyldimethylsilylchloride was added in several portions. The reaction was stirred at 0°C. for 1 hour and room temperature for 22 hours, then poured into water.The mixture was extracted with hexane, and the extract was washed withwater, dried over MgSO₄, and concentrated to give 52.51 g of theprotected intermediate. The intermediate was dissolved in 100 mL of THFand added via cannula to a flask containing 475 mL of DIBAL in 200 mL ofTHF at -78° C., then stirred for 15 min. The reaction was then warmed to0° rapidly and stirred for 2 hours. The reaction was quenched by slowlypouring it into 1L of satd. Na₂ SO₄. The mixture was filtered through afilter aid. The organic phase was separated and reserved. The aqueousphase was extracted with ether. The organic phases were combined, washedwith satd. brine, dried over MgSO₄ and concentrated to give a yellowliquid. This material was distilled in a kugelrohr apparatus at 0.2 mmHgand 70° C. to yield 19.50 g of the title product. [α]_(D) =-8.12° (26°C., c=2.02, CH2Cl2). ¹ H NMR (CDCl₃) ∂: 0.07 (s, 6H), 0.84 (d, 3H, J=7Hz), 0.90 (s, 9H), 1.94 (m, 1H), 2.81 (br, 1H), 3.54-3.62 (m, 3H), 3.74(m, 1H).

Step 279b. 2(R)-3-(t-butyldimethylsilyl)oxy-1-iodo-2-methylpropane

A 19.50 g (95.41 mmol) sample of2(R)-3-(t-butyldimethylsilyl)oxy-2-methyl-1-propanol, from step 279aabove, was dissolved in 100 mL of methylene chloride and 26.6 mL (191mmol) of triethylamine was added. The solution was cooled to 0° C., 11.0mL (142 mmol) of methansulfonyl chloride was added, and the reaction wasstirred for 1 hour. Stirring was discontinued, and the reaction was heldat -20° C. for 16 hours. The reaction was quenched with 5% NaHCO3, thenextracted with methylene chloride. The extract was washed with water,dried over MgSO₄ and concentrated. The residue was chromatographed ofsilica gel, eluting with melthylene chloride, and the solvent wasremoved to give 25.95 g of the mesylated intermediate. This intermediatewas dissolved in 100 mL of acetone, and 55 g of NaI was added. Themixture was heated at reflux for 10 hours, then cooled, diluted withhexane, and filtered. The filtrate was concentrated, the residueredissolved and refiltered, and again concentrated. The residue wasdistilled in a kugekohr apparatus at 0.2 mmHg and 60° C. to yield 18.22g of the title product. [α]_(D) =-9.39° (25° C., c=2.46, CH2Cl2). MS:332 (M+18)⁺, 315 (M+H)⁺. ¹ H NMR (CDCl₃) ∂: 0.07 (s, 6H), 0.60 (s, 9H),0.96 (d, 3H, J=7 Hz), 1.64 (m, 1H), 3.29 (m, 2H), 3.40 (m, 1H), 3.53 (m,1H).

Step 279c.3(S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyranol[2.3.4-ij]quinolizine-5-carboxylicacid hydrochloride

Following the procedure of Example 278d, substituting the2(R)-3-(t-butyldimethylsilyl)oxy-1-iodo-2-methylpropane of step 279babove for the 2(S)-3-(t-butyldimethylsilyl)oxy-1-iodo-2-methylpropane ofstep 278d, and carrying the product forward according to Example 278steps f-i, the title product was prepared. MS 362 (M-Cl)⁺. IR (KBr):3440, 1710, 1635, 1610 cm-1. ¹ H NMR (DMSO-d₆) ∂: 1.29 (d, 3H, J=7 Hz),2.82 (s, 3H), 3.18 (m, 2H), 3.27 (m, 1H), 3.48 (m, 2H), 3.69 (m, 2H),3.86 (m, 2H), 4.19 (dd, 1H, J=6, 11 Hz), 4.49 (dd, 1H, J=4, 11 Hz), 8.03(s, 1H), 9.03 (d, 1H, J=9 Hz), 11.09 (br, 1H), 13.96 (br, 1H). Anal calcfor C₁₈ H₂₀ FN₃ O₄.HCl.1.5H₂ O: C, 50.89; H, 5.69; N, 9.89; Found: C,50.50; H, 5.46; N, 9.72.

EXAMPLE 2809-fluoro-10-(1-morpholinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid

Step 280a. 3-(t-butyldimethylsilyloxy)-1-iodopropane

A mixture of 44.28 g (175 mmol) sample of1-bromo-3-(t-butyldimethylsilyloxy)-propane (prepared according toWilson and Zucker, J. Org. Chem, 33:2571 (1988)) and 100 g of NaI in 200mL of acetone was heated at reflux for 20 hours, filtered andconcentrated. The residue was dissolved in hexane, re-filtered andconcentrated. The residue was distilled in a kugelrohr apparatus(0.2-0.3 mm Hg, 60° C.) to give 46.87 g of the title product. Thismaterial was distilled under reduced pressure, and the pure productcoming over at 53°-57° C. and 0.3 mm Hg was collected. MS: 301 (M+H)⁺. ¹H NMR (CDCl₃) ∂: 0.70 (s, 6H), 0.90 (s, 9H), 1.99 (m, 2H), 3.28 (t, 2H,J=7 Hz), 3.66 (t, 2H, J=6 Hz).

Step 280b.9-fluoro-10-(1-morpholinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid

Following the procedure of Example 278d, replacing the(2S)-3-(t-butyldimethylsilyloxy)-1-iodo-2-methylpropane of that stepwith the 3-(t-butyldimethylsilyloxy)-1-iodopropane from step 280a above,and carrying the product forward according to the procedures of Examples278d-h, 20 mg of the title product was obtained. MS: 335 (M+1)⁺. IR(KBr): 3440, 1705, 1630, 1610 cm-1. ¹ H NMR (CDCl₃) ∂: 3.13 (t, 3H,J=5.5 Hz), 3.58 (m, 4H), 3.85 (m, 4H), 4.42 (t, 2H, J=5.5 Hz), 8.08 (s,1H), 8.94 (d, 1H, J=8.8 Hz). Anal. Calc. for C₁₆ H₁₅ FN₂ O₄ · 1/8H₂ O:C, 57.10; H, 14.57; N, 8.32; Found: C, 57.07; H, 14.32; N, 8.23.

EXAMPLE 281(3R)-10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5carboxylicacid

Step 281a.(2R)-3-(4-t-butoxy-3,5,6-trifluoro-2-pyridinyl)-2-methyl-1-propanol

A 9.38 g (29.85 mmol) of(S)-1-iodo-2-methyl-3-(t-butyldimethylsilyloxy)-propane, from Step 278babove, was dissolved in 50 mL of ether and reacted with 36.9 mL (1.7M inpentane, 62.73 mmol) of t-butyl lithium at -78° C. for 40 min and at 0°C. for 30 min. This solution was cooled to -78° C. again and added to astirred solution of 6.70 g (30.02 mmol) sample of4-t-butoxy-2,3,5,6-tetrafluoropyridine, from Example 274a above, in 40mL of ether at -78° C. The reaction was stirred for 5 min, the dry icebath was removed, and the reaction was stirred at room temperature for64 hours. The reaction was quenched with satd. NH4Cl, and the mixturewas extracted with ether. The extract was washed wtih satd. brine, driedover MgSO₄ and concentrated. The residue was dissoved in 20 mL of THF,and 30 mL of a 1N solution of tetrabutylammonium fluoride was added. Thereaction was stirred for 5 hours and concentrated. The residue wasdissolved in ether, which was washed with water, brine, dried overMgSO₄, and concentrated to dryness. The residue was flashchromatographed on silica gel, eluting with 1:3 acetone:hexane to give5.21 g of the title product as a colorless liquid after removal of thesolvent. MS: 278 (M+H)⁺. ¹ H NMR (CDCl₃) ∂: 0.93 (d, 3H, J-7 Hz), 1.44(s, 9H), 1.83 (t, 1H, J=7 Hz), 2.15 (m, 1H), 2.67 (m, 1H), 2.8 (m, 1H,3.50 (m, 2H). Anal. Calc. for C₁₃ H₁₈ F₃ NO₂. 1/4H₂ O: C, 55.41; H,6.62; N, 4.97; Found: C, 55.17; H, 6.30; N, 4.61.

Step 281 b.(2R)-3-(4-t-butoxy-3,5-difluoro-2-pyridinyl)-2-methyl-1-propanol

Following the procedure of Example 274b, replacing the reactant fromstep 278a with(2S)-3-(4-t-butoxy-3,5,6-trifluoro-2-pyridinyl)-2-methyl-1-propanol,from step 281a above, 3.44 g of the title product was prepared. MS: 260(M+H)⁺. ¹ H NMR (CDCl₃) ∂: 00.93 (d, 3H, J=7 Hz), 1.42 (m, 9H), 2.16 (m,1H), 2.86 (m, 2H), 2.96 (t, 1H, J=7 Hz), 3.40 (m, 1H), 3.53 (m, 1H),8.21 (m, 1H). Anal. Calc. for C₁₃ H₁₉ F₂ NO₂ : C, 60.22; H, 7.39; N,5.40; Found: C, 60.15; H 7.46; N, 5.22.

Step 281c.3(R)-7-fluoro-3-methyl-8-(t-butyloxy)-2,3-dihydro-4H-pyrano[3,2-b]pyridine

A 3.29 g (12.69 mmol) sample of(2R)-3-(4-t-butoxy-3,5-difluoro-2-pyridinyl)-2-methyl-1-propanol, fromstep 281b above, was dissolved in 100 mL of dioxane and added to adispersion of 0.570 g (19.00 mmol) of NaH (80% dispersion) in 100 mL ofdioxane. The mixture was heated at reflux for 4 hours, then concentratedto dryness. The residue was slurried with water, and extracted withether. The extract was washed with satd. brine, dried over MgSO₄, andconcentrated. The residue was purified by flash chromatography on silicagel, eluting with 1:2 ethyl acetete:hexane, to afford 2.722 g of thetitle product. MS: 240 (M+H)⁺. ¹ H NMR (CDCl₃) ∂: 1.08 (d, 3H, J=6.5Hz), 1.40 (d, 9H, J=1 Hz), 2.22 (m, 1H), 2.55 (m, 1H), 2.99 (m, 1H),3.69 (dd, 1H, J=9, 10 Hz), 4.21 (m, 1H), 8.01 (d, 1H, J=1 Hz). Analcalc. for C₁₃ H₁₈ FNO₂ : C, 66.25; H, 7.58; N, 5.85; Found: C, 66.35; H,7.49; N, 6.04.

Step 281d.3(R)-9-fluoro-10-hydroxy-3-methyl-2H,3H,6H-6-oxo-pyran[2.3.4-ij]quinolizine-5-carboxylicacid, ethyl ester

A 400 mg (1.671 mmol) sample of3(R)-7-fluoro-3-methyl-8-(t-butyloxy)-2,3-dihydro-4H-pyrano[3.2-b]pyridine,from step 281c above, was dissolved in 5 mL of THF and cooled to -78° C.To this solution was added a solution of 0.80 mL of n-butyl lithium (2.0mmol, 2.5M in hexane) and 0.28 mL of LDA (2.00 mmol) (prepared at -78°C. and warmed to 0° C. for 15 min), and the reaction was stirred at -78°C. for 30 min. To the reaction vessel was added 0.400 mL of diethoxyethoxymethylenemalonate, and the reaction was stirred for 5 min at -78°C. and at room temperature for 15 min. 1.7 mL of NNTMS2 (1N in THF) wasadded, the reaction was warmed to room temperature, then quenched withsatd. NH4Cl. The mixture was extracted with ether, which was washed,dried over MgSO₄ and concentrated. The solvent was removed, and theresidue was dissolved in 10 mL of ethanol. To this was added 0.5 mL ofDBU and thereaction was refluxed for 2 hours, then concentrated todryness. The residue was dissolved in methylene chloride, which was thenwashed with 10% citric acid, water, dried over MgSO₄, and concentrated.The residue was purified by chromatography on silica gel, eluting with100:10 methylene chloride:methanol. To the residue of the desiredfraction was added 3 mL of trifluoroacetic acid, and the mixture wasconcentrated immediately. The residue was washed with ether to leave307.4 mg of the title product as a yellow solid. MS: 308 (M+H)⁺. ¹ H NMR(DMSO-d₆) ∂: 1.25 (d, 3H, J=7 Hz), 1.27 (t, 3H, J=7 hz), 3.19 (m, 1H),4.10 (dd, 1H, J=5, 10 Hz), 4.22 (q, 2H, J=7 Hz), 4.33 (dd, 1H, J=4, 10Hz), 9.00 (d, 1H, J=8 Hz).

Step 281e.3(R)-10-chloro-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid, ethyl ester

A 276.1 mg (0.899 mmol) sample of3(R)-9-fluoro-10-hydroxy-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid, ethyl ester, from step 281d above, was dissolved in 5 mL ofmethylene chloride, and 0.71 mL (9.17 mmol) of DMF and 0.85 mL of POCl₃(9.12 mmol) were added. The reaction was stirred for 15 hours andquenched with water and ice. The mixture was extracted with methylenechloride, and the extract was washed with water, dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography on silicagel, eluting with 10:1 methylene chloride:methanol to afford 180.6 mg ofthe title product as a yellow solid after removal of the solvent. MS:326, 328 (M+H)⁺. ¹ H NMR (CDCl₃) ∂: 1.40 (d, 3H, J=5 hz), 1.43 (t, 3H, 7Hz), 3.22 (m, 1H), 4.21 (dd, 1H, J=6, 10 Hz), 4.45 (m, 3H), 8.25 (s,1H), 9.09 (d, 1H, J=6 Hz).

Step 281f.3(R)-10-(3-(N-BOC)amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid, ethyl ester

A 130.9 mg (0.402 mmol) sample of3(R)-10-chloro-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid, ethyl ester, from step 281e above, was dissolved in 5 mL ofacetonitrile. To this solution was added 0.24 mL of DBU and 120 mg(0.644 mmol) of 3-(N-BOX)aminopyrrolidine (TCI America, Inc.), and thereaction was heated at reflux for 8 hours. The solvent was removed, andthe residue was dissolved in methylene chloride which was washed withwater. The solvent was removed and the residue was purified by flashchromatography on silica gel, eluting with 100:10:0.5-methylenechloride:methanol:NH₄ OH to afford 187.6 mg of the title product as ayellow solid.

Step 281g.3(R)-10-(3-(N-BOC)amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid

A 187.6 mg (0.394 mmol) sample of3(R)-10-(3-(N-BOC)amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid, ethyl ester, from step 281f above, was dissolved in 4 mL of THFand 70 mg of LiOH.H₂ O in 2 mL of water was added. The mixture wasstirred under N₂ for 8 hours at 60° C. The pH was adjusted to 6.5 with1N HCl, and the mixture was extracted wtih methylene chloride. Theextract was washed with water, dried over MgSO₄ and concentrated. Theresidue was purified by flash chromatography on silica gel, eluting with100:10:1 methylene chloride:methanol:acetic acid to afford 144 mg of thetitle product as a yellow solid. MS: 448 (M+H)⁺. IR (KBr): 3440, 1710,1640, 1610 cm⁻¹. ¹ H NMR (CDCl₃) ∂: 1.32 (d, 3H, J=7 Hz), 1.47 (s, 9H),2.00 (m, 1H), 2.18 (m, 1H), 3.11 (m, 1H), 3.85 (m, 1H), 3/987 (m, 2H),4.10-4.16 (m, 2H), 4.26 (m, 1H), 4.32 (m, 1H), 5.06 (m, 1H), 7.92 (s,1H), 8.80 (d, 1H, j=10 Hz). Anal calc. for C₂₂ H₁₆ FN₃ O₆.H₂ O: C,56.77; H, 6.06; N, 9.03; Found: C, 56.70; H, 5.80; N, 8.81.

Step 281h.3(R)-10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid hydrochloride

A 115.7 mg (0.259 mmol) sample of3(R)-10-(3-(N-BOC)amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid, from step 281g above, was dissolved in 3 mL of 4N HCl in dioxane,and the reaction was stirred for 1.5 hours at room temperature. Thesolution was concentrated to dryness, and the residue was dried in avacuum. The residue was dissolved in water, filtered though sinteredglass, and freeze-dried to give 97.3 mg of the title product as a yellowsolid. MS: 348 (M-Cl)⁺. IR (KBr): 3440, 1690, 1640, 1600 cm⁻¹. ¹ H NMR(DMSO-d₆) ∂: 1.27 (d, 3H, J=7 Hz)), 2.10 (m, 1H), 2.22 (m, 1H), 3.20 (m,1H), 3.88 (m, 1H), 3.99 (m, 2H), 4.10-4.16 (m, 3H), 4.27 (m, 1H), 7.82(s, 1H), 8.95 (d, 1H, J=10 Hz). Anal calc. for C₁₇ H₁₈ FN₃ O₄.0.5H₂O.2HCl: C, 47.57; H, 4.93; N, 9.79; Found: C, 47.72; H, 4.81; N, 9.58.

Step 281i.3(R)-10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid

A 50 mg sample of the hydrochloride salt from step 281h was dissolved in5 mL of water, and satd. NaHCO3 was adde until the solution was pH 7.The solid (27.8 mg) was collected by filtration, and the filtrate wasextracted with 10% methanol in methylene chloride and methylenechloride. The extract was washed, dried and concentrated to afford asecond crop of product. MS: 348 (M+H)⁺. IR (KBr): 3440, 1650, 1640, 1600cm³¹ 1. ¹ H NMR (DMSO-d₆) ∂: 1.25 (d, 3H, J=7 Hz), 1.68 (m, 1H), 1.95(m, 1H), 3.16 (m, 1H), 3.55 (m, 2H), 3.94-4.05 (m, 4H), 4.25 (m, 1H),7.74 (s, 1H), 8.89 (d, 1H, J=11 Hz). Anal calc. for C₁₇ H₁₈ FN₃ O₄·1.5H₂ O: C, 54.54; H, 5.57; N, 11.23; Found: C, 54.78; H, 5.31; N,11.05.

EXAMPLE 2823(R)-10-(3-aminomethyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid hydrochloride

Following the procedure of Example 281f, replacing the the3-(BOC-amino)pyrrolidine of that step with3-(BOC-amino)methylpyrrolidine (prepared according to EP Publishedapplication 0106489), and carrying the product forward according tosteps 281g and h, 118 mg of the title compound was prepared. MS: 362(M-Cl)⁺. IR (KBr): 3440, 1640, 1600 cm⁻¹. ¹ H NMR (DMSO-d₆) ∂: 1.25 (d,3H, J=7 Hz), 1.72 (m, 1H), 2.10 (m, 1H), 2.53 (m, 1H), 2.94 (m, 2H),3.16 (m, 1H), 3.76 (m, 1H), 3.96 (m, 2H), 4.05 (m, 2H), 4.25 (m, 1H),7.77 (s, 1H), 8.12 (br, 4H), 8.90 (d, 1H, J=10 Hz), 13.92 (br, 1H). Analcalc. for C₁₈ H₂₆ FN₃ O₄ ·2HCl: C, 49.78; H, 5.11; N, 9.68; Found: C,49.90; H, 5.04; N, 9.74.

EXAMPLE 2833(R)-10-((2S,4S)-4-amino-2-methyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid hydrochloride

Following the procedure of Example 281f, replacing the the3-(BOC-amino)pyrrolidine of that step with(2S,4S)-4-BOC-amino-2-methylpyrrolidine (from Example 171, step 5), andcarrying the product forward according to steps 281g and h, 57 mg of thetitle compound was prepared. MS: 362 (M-Cl)⁺. IR (KBr): 3440, 1700,1635, 1610 cm⁻¹. ¹ H NMR (DMSO-d₆) ∂: 1.20 (d, 3H, J=6 Hz), 1.28 (d, 3H,J=7 Hz), 1.92 (m, 1H), 2.37 (m, 1H), 3.22 (m, 1H), 3.77 (m, 1H), 3.91(m, 1H), 4.09 (m, 1H), 4.34 (m, 2H), 4.82 (m, 1H), 7.88 (s, 1H), 8.28(br, 4H), 9.00 (d, 1H, J=10 Hz), 13.94 (br, 1H). Anal calc. for C₁₈ H₂₆FN₃ O₄.2HCl: C, 49.78; H, 5.11; N, 9.68; Found: C, 49.78; H, 5.04; N,9.73.

EXAMPLE 2843(R)-9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid

Following the procedure of Example 281f, replacing the the3-(BOC-amino)pyrrolidine of that step with (3-hydroxypyrrolidine(Aldrich Chemical Co.), and carrying the product forward according tostep 281g, 69 mg of the title compound was prepared. MS: 349 (M+H)⁺. ¹ HNMR (DMSO-d₆) ∂: 1.24, 1.26 (two d, 3H, J=6 Hz), 1.80 (m, 2H), 3.16 (m,1H), 3.69 (m, 1H), 3.92 (m, 1H), 4.06 (m, 3H), 4.26 (dd, 1H, J=10, 4Hz), 4.36 (m, 1H), 5.09 (d, 1H, J=3 Hz), 7.76 (s, 1H), 8.90 (d, 1H, J=10Hz), 13.94 (br, 1H). Anal calc. for C₁₇ H₁₇ FN₂ O₅ : C, 58.62; H, 4.92;N, 8.04; Found: C, 58.23; H, 4.91; N, 7.81.

EXAMPLE 2859-fluoro-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid hydrochloride

Step 285a.9-fluoro-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid

Following the procedure of Example 281f, replacing the the3-(BOC-amino)pyrrolidine of that step with N-methylpiperazine (AldrichChemical Co.), and carrying the product forward according to step 281fand Example 278 step h, 69 mg of the title compound was prepared. MS:348 (M+H)⁺. ¹ H NMR (CDCl₃) ∂: 2.39 (s, 3H), 2.57 (m, 4H), 3.12 (t, 2H,J=6 Hz), 3.60 (m, 4H), 4.40 (t, 2H, J=6 Hz), 8.10 (s, 1H), 8.94 (d, 1H,J=9 Hz), 13.87 (s, 1H). Anal calc. for C₁₇ H₁₈ FN₃ O₄.0.5H₂ O; C, 57.30;H, 5.37; N, 11.79; Found: C, 57.71; H, 5.23; N, 11.41.

Step 285b.9-fluoro-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]-quinolizine-5-carboxylicacid hydrochloride

Following the procedure of Example 278i, replacing the compound of step278h with the9-fluoro-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylicacid, from step 285a above, the title compound was prepared.

EXAMPLES 286-296

Following the procedures of Steps 253j, 253k and 253l (if required),above, replacing the 3-BOC-aminopyrrolidine of Step 253j with thereagent shown, the compounds of Examples 286-296 are prepared as shownin Table 11, below.

                                      TABLE 11                                    __________________________________________________________________________     ##STR193##                                                                   Ex. No.                                                                            Reagent                  R.sup.2                                         __________________________________________________________________________    286  1,3-dimethylpiperazine                                                                                  ##STR194##                                     287  3-(NBOCN-methyl)aminopiperidine                                                                         ##STR195##                                     288  2-(NBOC-aminomethyl)morpholine                                                                          ##STR196##                                     289  3(S)-(NBOCN-methylamino)-pyrrolidine                                                                    ##STR197##                                     290  3-((NBOCN-methylamino)methyl)-pyrrolidine                                                               ##STR198##                                     291  3-((NBOCN-ethylamino)methyl)-prrolidine                                                                 ##STR199##                                     292  2-BOC-octahydropyrrolo[3,4-c]pyrrole                                                                    ##STR200##                                     293  5-BOC-octahydropyrrolo[3,4-c]pyridine                                                                   ##STR201##                                     294  cis-3-BOC-amino-4-methylpyrrolidine                                                                     ##STR202##                                     295  trans-3-BOC-amino-4-methylpyrrolidine                                                                   ##STR203##                                     296  7-amino-5-azaspiro[2.4]heptane                                                                          ##STR204##                                     __________________________________________________________________________

EXAMPLE 2978-(2S,4S-4-amino-2-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-(fluoro)methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253c, reacting the product of Step253b with LDA at -78° C., then adding formaldehyde and stirring untilthe reaction is complete, followed by reaction of the newly formedintermediate with diethylaminosulfur trifluoride (DAST) in methylenechloride to form the intermediate product4-t-butoxy-2,3,6-trifluoro-5-(fluoro)methylpyridine, and carrying thisproduct through the remaining steps as in Example 253d-l, the titlecompound is prepared.

EXAMPLE 298 8-(3-Dimethylaminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid,acetic acid salt

A 81 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 2.5 mL ofdry pyridine under a nitrogen atmosphere. To this solution was added asolution of 114 g of 3-(dimethylamino)pyrrolidine in 2.5 mL of pyridine,and the reaction mixture was heated at 60° C. for 39 hours. The pyridinewas removed under vacuum, and the residue was stirred with 1N NaOH inTHF/water for at 60° C. for 6 hours. The solution was made acidic withacetic acid, and the product was extracted with chloroform. After dryingover MgSO₄, the solvent was removed, and the residue was purified bychromatography on silica gel, eluting with 100:40:20:8 chloroform:methanol: acetic acid:water to give the title product. mp 165°-170° C.(dec.). MS 374 (M+H)⁺ ; ¹ H NMR (D₆ -DMSO) ∂: 0.53 (m, 2H), 0.82-1.08(m, 2H), 1.75 (s, 3H), 2.22 (s, 6H), 2.08-2.33 (m, 2H), 2.74 (m, 2H),3.44-3.94 (m, 5H), 8.01 (br s, 1H), 8.90 (br s, 1H).

EXAMPLE 299(3R)-8-(3-Dimethylaminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 298, replacing the3-(dimethylamino)pyrrolidine with (3R)-3-(dimethylamino)pyrrolidine, thetitle compound was prepared. mp 146°-148° C. MS 374 (M+H)⁺ ; ¹ H NMR (D₆-DMSO) ∂: 0.64 (m, 2H), 1.02 (m, 2H), 2.23-243 (m, 3H), 2.66 (s, 3H),2.83 (s, 6H), 3.78-4.17 (m, 5H), 7.95 (s, 1H), 9.12 (d, 1H, J=11 Hz),11.14 (br s, 1H), 13.83 (br s, 1H).

EXAMPLE 300 (3R,1S)-8-(3-(1-Aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in anhydrousacetonitrile, reacted with(3R,1S)-3-(1-(t-butoxycarbonylamino)ethyl)pyrrolidine (prepared asdescribed by Schroeder et at., J. Heterocyclic Chem., 29:1481-1498(1992)), and carried forward as described in Example 253k-l to give thetitle product. mp 250°-255° C. (dec.). MS 374 (M+H)⁺ ; ¹ H NMR (D₆-DMSO) ∂: 0.59 (m, 2H), 1.00 (m, 2H), 1.29 (d, 3H, J=6 Hz), 1.77 (m,1H), 2.13 (m, 1H), 2.29 (m, 1H), 2.41 (m, 1H), 2.64 (s, 3H, 3.57 (s,1H), 3.76 (m, 3H), 3.94 (m, 1H), 7.91 (s, 1H), 8.17 (brs, 3H), 9.07 (d,1H, J=11 Hz), 13.83 (brs, 1H).

EXAMPLE 301 (3S,1R)-8-(3-(1-Aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A 0.44 g sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, and 1.51 g of NaHCO₃ weredissolved in 40 mL of anhydrous acetonitrile, reacted with(3S,1R)-3-(1-(t-butoxycarbonylamino)ethyl)pyrrolidine (1.06 g, preparedas described by Schroeder et al., J. Heterocyclic Chem., 29:1481-1498(1992)), and carried forward as described in Example 253k-l to give thetitle product. mp 235°-240° C. (dec.). MS 374 (M+H)⁺ ; ¹ H NMR (D₆-DMSO) ∂: 0.59 (m, 2H), 1.00 (m, 2H), 1.29 (d, 3H, J=6 Hz), 1.76 (m,1H), 2.13 (m, 1H), 2.28 (m, 1H), 2.41 (m, 1H), 2.63 (s, 3H), 3.30 (m,1H), 3.74 (m, 3H), 3.94 (m, 1H), 7.90 (s, 1H), 8.16 (br s, 3H), 9.07 (d,1H, J=11 Hz).

EXAMPLE 302(3R,1R)-8-(3-(1-Aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A 0.35 g sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, and 0.73 g of sodiumbicarbonate were dissolved in 24 mL of anhydrous acetonitrile, reactedwith (3R, 1R)-3-(1-(t-butoxycarbonylamino)ethyl -pyrrolidine (0.51 g,prepared as described by Schroeder et al., J. Heterocyclic Chem.,29:1481-1498 (1992)), and carried forward as described in Example 253k-lto give the title product. mp 220°-222° C. MS 374 (M+H)⁺ ; ¹ H NMR (D₆-DMSO) ∂: 0.61 (m, 2H), 0.94 (m, 1H), 1.07 (m, 1H), 1.28 (d, 3H, J=6Hz), 1.82 (m, 1H) 2.27 (m, 2H), 2.46 (m, 1H), 2.62 (s, 3H), 3.57 (s,1H), 3.92 (m, 1H), 7.90 (s, 1H), 8.17 (br s, 3H), 9.07 (d, 1H, J=11 Hz),13.84 (brs, 1H).

EXAMPLE 3031-cyclopropyl-8-((R,S)-3-fluoropyrrolidine)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid

303a. N-CBZ-(R,S)-3-hydroxypyrrolidine

(R,S)-3-hydroxypyrrolidine (1.0 g, 0.011 mmol) was dissolved in ethylacetate (50 mL) and to this solution at room temperature was addedN-(benzyloxycarbonyl)succinimide (2.86 g, 0.011 mmol). The mixture wasstirred overnight then partitioned between dilute aqueous HCl and ethylacetate. The aqueous phase was extracted with ethyl acetate (2×). Theorganics were combined, dried (MgSO₄) and concentrated in vacuo. Thecrude product was purified by flash chromatography on silica gel (ethylacetate-hexane) to give the desired compound as a clear oil, 2.1 g, 83%.MS (DCI/NH₃) m/z: 222 (M+H)⁺, 239 (M+NH₄)⁴ ¹ H NMR (CDCl₃) ∂: 1.85-2.10(m, 2H), 3.37-3.65 (m, 4H), 4.44-455 (m, 1H), 5.15 (s,2H), 7.28-7.45 (m,5H).

303b. N-CBZ-(R,S)-3-fluoropyrrolidine

The compound from step 303a above (32.01 gm, 9.10 mmole) was dissolvedin anhydrous CH₂ Cl₂ (40 mL) and cooled under nitrogen to -78° C. To thecold solution was added in one portion via syringe diethylaminosulfurtrifluoride (DAST) (1.32 mL, 10.0 mmol), and the resulting solution wasstirred overnight at room temperature. The product was isolated byconcentrating the reaction mixture in vacuo with flash chromatography ofthe residue on silica gel(ethyl acetate-hexane) to give a clear oil,1.53gm, 75%. MS (DCI/NH₃) m/z: 224 (M+H)⁺, 241 (M+NH₄)⁺ 1 H NMR (CDCl₃)∂: 1.83-2.15 (m, 1H), 216-2.35 (m, 1H), 3.43-3.90 (m, 4H), 5.21-5.24 (m,2.5H) 5.28-5.36, (m, 0.5H), 7.28-7.5 (m5H).

303c. (R,S)-3-fluoropyrrolidine hydrochloride

The compound from step 303b above (1.53 g, 6.85 mmol) was dissolved inmethanol (50 mL) to which was added 5% Pd/BaSO₄ (0.5g). The mixture wasvacuum degassed (3×) then exposed to a low pressure atmosphere ofhydrogen (balloon) at room temperature for 4 hours. The reaction wasterminated by vacuum filtration to remove catalyst. The filtrate wascooled in an ice bath, then HCl gas was bubbled into the cold solutionfor one minute. The resulting solution was concentrated in vacuo, andthe residue was triturated with ethyl acetate-ether. The solid wascollected by vacuum filtration to give 0.659 g, 76%, of thehydrochloride as an off white solid. ¹ HNMR (CD₃ OD) d: 2.1-2.46 (m,2H), 3.33-3.65 (m, 4H), 5.43 (db.t., 1H, J_(F),H =51 Hz).

303d.1-cyclopropyl-8-((R,S)-3-fluoropyrrolidine)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid

The N-boc-3-aminopyrrolidine of Example 253j above was replaced by the(R,S)-3-fluoro pyrrolidine hydrochloride of step 303c above (0.66 g,5.24 mmol), and the reaction product was carried forward as previouslydescribed to give 0.326 g (65%) of the title compound as a bright yellowsolid. mp 227.5°-230° C. (dec.). MS (DCI/NH₃) m/z: 349 (M+H)⁺. ¹ HNMR(CDCl₃) d: 0.58-0.78 (cm, 2H), 0.85-0.98, (cm, 1H) 1.04-1.16 (cm,1H), 2.03-2.53 (cm, 3H), 2.67 (s,3H), 3.60-3.86 (cm, 2H), 4.05-4.26 (cm,2H), 5.43 (db.t, 1H, J_(F),H =52 Hz), 7.26 (s, 1H), 8.26 (s, 1H), 8.26(s, 1H), 9.08 (d, 1H, J=10.5 Hz), 13.8 (br.s., 1H). Calc. for C₁₈ H₁₈ N₂O₃ F₂ : % C, 62.05; H, 5.22; N, 8.04. Found: % C, 62.06; H 5.22; N,7.86.

EXAMPLE 3048-(4-(1-piperidyl)-1-piperidyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid

A 70 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 2 mL ofanhydrous acetonitrile, reacted with 4-(1-piperidyl)piperidine (70 mg,0.4 mmol, Aldrich Chem. Co.), and carried forward as described inExample 253j-k to give the title product. MS 428 (M+H)⁺ ; ¹ H NMR(CDCl₃) ∂: 0.69 (m, 2H), 1.02 (m, 2H), 1.18 (m, 4H), 2.27 (n, 1H), 2.78(s, 3H), 2.72 (m, 1H), 3.35 (m, 3H), 3.55 (m, 1H), 3.75 (m, 1H), 8.36(s, 1H), 9.20 (d, 1H). Anal. Calcd for C₂₄ H₃₀ N₃ O₃ F.1.5 H₂ O: C,63.42; H, 7.32; N, 9.24; Found: C, 62.99; H, 7.04; N, 8.78.

EXAMPLE 3058-(4-(1-piperidyl)-1-piperidyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid trifluoroacetic acid salt

A 100 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 3 mL ofanhydrous acetonitrile, reacted with 4-(4-piperidyl)-piperidine (0.24 g,0.93 mmol, obtained from Aldrich Chem. Co.), carried forward asdescribed in Example 253j-k and converted to the TFA salt by theprocedure of Example 162 to give the title product. MS 428 (M+H)⁺ ; ¹ HNMR (CDCl₃) ∂: 0.69 (m, 2H), 1.03 (m, 2H), 1.70 (m, 2H), 1.87 (m, 2H),1.98 (m, 2H), 2.14 (m, 2H), 2.27 (m, 1H), 2.77 (s, 3H), 2.91 (m, 2H),3.33 (m, 2H), 3.54 (m, 4H), 8.37 (s, 1H), 9.21 (d, 1H). Anal. Calcd forC₂₄ H₃₀ N₃ O₅ F₄.1.5 H₂ O: C, 54.93; H, 6.03; N, 7.39; Found: C, 54.97;H, 5.39; N, 7.24.

EXAMPLE 3068-(4-(2-pyridyl)-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid

A 60 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 2 mL ofanhydrous acetonitrile, reacted with 4-(2-pyridyl)piperazine (63.5 mg,0.39 mmol, Aldrich Chem. Co.), and carried forward as described inExample 253j-k to give the title product. MS 423 (M+H)⁺ ; ¹ H NMR(CDCl₃) ∂: 0.71 (m, 2H), 1.05 (m, 2H), 2.30 (m, 1H), 2.86 (s, 3H), 3.59(m, 4H), 3.78 (m, 4H), 6.76 (m, 2H), 7.57 (m, 1H), 8.25 (m, 1H), 8.40(s, 1H), 8.25 (d, 1H), 13,83 (bs, 1H). Anal. Calcd for C₂₃ H₂₃ N₄ O₃F.1.5 H₂ O: C, 61.46; H, 5.83; N, 12.46; Found: C, 61.76; H, 5.54; N,11.64.

EXAMPLE 3078-((2-amino)thioethoxy)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid trifluoroacetic acid salt

A 50 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 2 mL ofanhydrous acetonitrile, reacted with N-BOC-2-aminothiol (57.4 mg, 0.32mmol, prepared by standard procedures from the unprotected compoundobtained from Aldrich Chem. Co.), carried forward as described inExample 253j-k, deprotected as in step 253l, and converted to the TFAsalt by the procedure of Example 162 to give the title product. MS 337(M+H)⁺ ; ¹ H NMR (d₆ -DMSO) ∂: 0.74 (m, 2H), 1.08 (m, 2H), 3.04 (t, 2H),3.16 (s, 3H), 3.33 (t, 2H), 8.27 (s, 1H), 9.32 (d, 1H), 13.8 (br, 1H).

EXAMPLE 308(3R,1S)-8-(3-(1-amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A 147 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 3 mL ofanhydrous acetonitrile, reacted with(3R,1S)-3-(1-BOC-amino)propyl)pyrrolidine (326 mg, 1.13 mmol, preparedas described by Hayakawa et al., U.S. Pat. No. 5,098,912, issued Mar.24, 1992, using modifications for chiral products described by Plummeret al. Tetr. Lett. 34:7529-32 (1993)), and carried forward as describedin Example 253j-l to give the title product. MS (high resolution) found:388.2039; calc: 388.2036 (M+H)⁺ ; ¹ H NMR (D₆ -DMSO) ∂: 0.60 (m, 2H),1.00 (t, 3H), 1.01 (m, 2H), 1.63 (m, 2H), 2.13 (m, 1H), 2.29 (m, 2H),3.73 (m, 3H), 3.95 (m, 1H), 7.96 (s, 1H), 8.00 (b m, 2H), 9.08 (d, 1H),13.83 (b s, 1H). Anal. Calcd for C₂₁ H₂₇ N₃ O₃ FCl.0.5 H₂ O: C, 58.13;H, 6.74; N, 9.68; Found: C, 58.24; H, 6.51; N, 9.71.

EXAMPLE 309(3R,1S)-8-(3-(1-(N-methy)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A 492.9 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 8 mL ofanhydrous acetonitrile, reacted with(3R,1S)-3-(1-(N-methyl)amino)propyl)pyrrolidine (501 mg, 3.53 mmol,prepared as described by Hayakawa et al., U.S. Pat. No. 5,098,912,issued Mar. 24, 1992, using modifications for chiral products describedby Plummer et al. Tetr. Lett. 34:7529-32 (1993)), and carried forward asdescribed in Example 253 j-l, omitting the deprotecting step, to givethe title product. MS 402 (M+H)⁺ ; ¹ H NMR (D₆ -DMSO) ∂: 0.61 (m, 2H),0.98 (t, 3H), 1.00 (m, 2H), 1.75 (m, 5H), 2.15 (m, 1H), 2.30 (m, 1H),2.59 (s, 3H), 2.63 (s, 3H), 3.66 (m, 1H), 3.77 (m, 2H), 3.95 (m, 1H),7.90 (s, 1H), 8.60 (bs, 2H), 9.08 (d, 1H), 13.83 (bs, 1H) Anal. Calcdfor C₂₂ H₂₉ N₃ O₃ FCl.H₂ O: C, 57.95; H, 6.85; N, 9.22; Found: C, 58.24;H, 6.58; N, 9.30.

EXAMPLE 310(3R,1S)-8-(3-(1-amino-3-methylpropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A 171 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 4 mL ofanhydrous acetonitrile, reacted with(3R,1S)-3-(1-amino-3-methylpropyl)pyrrolidine (400 mg, 1.32 mmol,prepared as described by Plummer et al., Tetr. Lett. 34:7529-32 (1993),and carried forward as described in Example 253j-l, omitting thedeprotection reaction, to give the title product. MS (high resolution)found: 402.2174; calc: 402.2193 (M+H)⁺ ; ¹ H NMR (D₆ -DMSO) ∂: 0.60 (m,2H), 0.95 (d, 3H), 1.06 (d, 3H), 1.75 (m, 1H), 2.13 (m, 1H), 229 (m,2H), 2.50 (s, 3H), 3.66 (m, 3H), 3.78 (m, 1H), 3.97 (m, 1H), 7.88 (s,1H), 908 (d, 1H), 13.82 (bs, 1H). Anal. Calcd for C₂₂ H₂₉ N₃ O₃ FCl.0.75H₂ O: C, 58.53; H, 6.81; N, 9.31; Found: C, 58.88; H, 6.70; N, 9.26.

EXAMPLE 3118-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine3-carboxylicacid hydrochloride

A 98 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 2 mL ofanhydrous acetonitrile, reacted with1-(N-BOC-amino)cyclopropyl)pyrrolidine (172 mg,0.76 mmol, prepared asdescribed by Hayakawa et al., U.S. Pat. No. 5,098,912, issued Mar. 24,1992), and carried forward as described in Example 253j-l to give thetitle product. MS (high resolution) found: 386.1893; calc: 386.1880(M+H)⁺ ; ¹ H NMR (D₆ -DMSO) ∂: 0.60 (m, 2H), 0.91 (m, 5H), 1.04 (m, 1H),1.67 (m, 1H), 2.04 (m, 1H), 2.29 (m, 2H), 2.61 (s, 3H), 370 (m, 3H),3.93 (m, 1H), 7.90 (s, 1H), 8.43 (bs, 2H), 9.08 (d, 1H), 13.82 (s, 1H).Anal. Calcd for C₂₂ H₂₉ N₃ O₃ FCl: C, 59.55; H, 6.12; N, 9.80; Found: C,59.78; H, 5.97; N, 9.69.

EXAMPLE 312(3R,1S)-8-(3-(1-amino-2-hydroxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Step 312a. (S)-N-BOC-O-(methoxymethyl)serine methyl ester

A 7 g (31.96 mmol) sample of ((S)-N-BOC-serine methyl ester (obtainedfrom Aldrich) was dissolved in CH₂ Cl₂ and cooled in an ice bath. Tothis stirred solution was added dropwise 2.83 g (35.16 mmol) ofmethoxymethyl chloride, followed by dropwise addition of 4.544 g (6.12mL, 35.16 mmol) of diisopropylethylamine. After all reagents were addedthe reaction was stirred for 16 hours at room temperature. The solutionwas washed with 0.5% HCl, satd. NaHCO₃, H₂ O, and brine, dried overMgSO₄ and filtered. The solvent was removed to leave a yellow oil. Theresidue was purified by chromatography on silica gel, eluting with15-20% ethyl acetate:hexane to afford 6 g of title product after removalof the solvent. MS 264 (M+H)⁺ ; ¹ H NMR (CDCl₃) ∂: 1.47 (s, 9H), 3.31(s, 3H), 3.74 (dd, 1H), 3.79 (s, 3H), 4.00 (dd, 1H), 4/45 (b M, 1H),4.60 (s, 2H), 5.43 (b m, 1H).

Step 312b. 2-(BOC-amino)-3-(methoxymethoxy)-1-propanol

A solution of the compound from step 312a above (5.202 g, 19.78 mmol) in15 mL of THF was added dropwise to a cooled (ice bath) suspension of 570mg (14.84 mmol) of LAH in 15 mL of THF under N₂ atmosphere. The mixturewas stirred for 1.5 hours, the reaction was quenched with water and 50%NaOH, filtered, and the filtrate evaporated to obtain the crude product.A yellow oil was obtained, which was purified by chromatography onsilica gel, eluting with 35-40% ethyl acetate:hexane to give 3.475 g ofthe title product as a colorless oil. MS 236 (M+H)⁺.

Step 312c. 2-(BOC-amino)-3-(methoxymethoxy)-1-propanal

To a solution of the compound from step 312b above (3.47 g, 14.77 mmol)in 7 mL of DMSO cooled to 0° C. was added dropwise 6.8 mL (48.74 mmol)of triethylamine. Pyridine.SO₃ complex (7.05 g, 44.31 mmol) wasdissolved in 27 mL of DMSO and added to the first solution, and thereaction was stirred for one hour after the addition was complete. Thesolution was poured into 120 mL of cold brine, and the mixture waswashed 3× with ethyl acetate. The extract was washed with water, driedover MgSO4, filtered and the solvent was removed under vacuum to give 6g of a yellow oil, which was taken directly to the next step.

Step 312d. 4-(BOC-amino)-5-(methoxymethoxy)-2-pentenoic acid ethyl ester

To a solution of the compound from step 312c above (14.77 mmol) in 42 mLof CH₂ Cl₂ and cooled in an ice bath was added dropwise 5.454 g (15.66mmol) of (carboethoxymethylene)triphenylphosphorane in 56 mL of CH₂ Cl₂.After addition was complete, the reaction was stirred for 16 hours atroom temperature. The solvent was removed, and the residue purified bycolumn chromatography on silica gel, eluting with 10% ethylacetate:hexane, to give 2.763 g of a colorless oil. MS 304 (M+H)⁺ ; ¹ HNMR (CDCl₃) ∂: 1.25 (t, 3H), 1.47 (s, 9H), 3.36 (s, 3H), 3.67 (dd, 1H),3.73 (dd, 1H), 3.72 (m, 1H), 4.20 (q, 2H), 4.62 (s, 2H), 5.99 (dd, 1H),6.93 (dd, 1H).

Step 312e. 4-(BOC-amino)-5-(methoxymethoxy)-3-(nitromethyl)-pentanoicacid ethyl ester

To a solution of the compound from step 312d above (2.76 g, 9.71 mmol)in 8 mL of nitromethane cooled in an ice bath was added 7 mL (6.934 g,45.55 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene dropwise under N₂. Themixture was warmed to room temperature and stirred for 16 hours. Thesolution was diluted with CH₂ Cl₂ and extracted with water, 10% HCl, 10%NaHCO₃, water and brine. The solution was dried over MgSO4, and thesolvent was removed. The residue was chromatographed on silica gel,eluting with 10-15% ethyl acetate:hexane, and the solvent was removed togive 2.01 g of the title product as a white solid. MS 365 (M+H)⁺ ; ¹ HNMR (CDCl₃) ∂: 1.27 (t, 3H), 1.47 (s, 9H), 2.46 (dd, 1H), 2.98 (br, 1H),3.38 (s, 3H), 3.58 (ddd, 1H), 3.76 (dd, 1H), 3.97 (b m, 1H), 4.16 (q,1H), 4.53 (dd, 1H), 4.62 (s, 2H), 4.67 (dd, 1H), 4.99 (b d, 1H).

Step 312f. 4-(BOC-amino)-5-(methoxymethoxy)-3-(aminomethyl)-pentanoicacid ethyl ester

Two g of the compound from step 312e above was dissolved in 200 mL ofethanol and hydrogenated at 4 Atm over 4 g of Raney nickel catalyst for24 hours. The catalyst was removed by filtration and the solvent wasevaporated. The residue was taken directly to the next step.

Step 312g. N-BOC-2-(methoxymethoxy)-1-(5-oxo-3-pyrrolidinyl)-ethylamine

The residue from step 312f above was dissolved in 150 mL of ethanol andheated at reflux for 8 hours. The solvent was removed, the residue waschromatographed on silica gel, eluting with 4% methanol/methylenechloride. Removal of the solvent gave 1.36 g of title product. MS 289(M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 1.47 (t, 3H), 2.17 (dd, 1H), 2.38 (dd, 1H),2.78 (m, 1H), 3.31 (t, 1H), 3.46 (s, 3H), 3.46 (t, 1H), 3.59 (m, 2H),3.81 (b t, 1H), 4.62 (s, 2H), 4.94 (br d, 1H), 5.43 (br, 1H).

Step 312h.N-BOC-2-(methoxymethoxy)-1-(5-thioxo-3-pyrrolidinyl)-ethylamine

A 500 mg (1.74 mmol) sample of the compound from step 312g above and 387mg (0.957 mmol) of Lawesson's reagent were dissolved in 4 mL of THF andstirred under N₂ for 3 hours. The solvent was removed, and the residuewas dissolved in CH₂ Cl₂ and chromatographed on silica gel, eluting with35% ethyl acetate:hexane. Removal of the solvent left 500 mg of product.MS 305 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 1.47 (s, 9H), 2.71 (dd, 1H), 2.89 (m,1H), 3.00 (dd, 1H), 3.37 (s, 3H), 3.53 (dd, 2H), 3.66 (m, 2H), 3.83 (bm, 1H), 4.61 (s, 2H), 4.98 (b d, 1H).

Step 312i. N-BOC-2-(methoxymethoxy)-3-pyrrolidinyl)-ethylamine aceticacid salt

A 250 mg (0.825 mmol) sample of the compound from step 312h above and1.57 g (6.6 mmol) of NiCl2.6H₂ O were dissolved in 10 mL of a 1:1mixture of methanol and THF, and the solution was cooled to -78° C. andstirred under N₂. A 749 mg (19.8 mmol) sample of NaBH₄ was added inportions, and the mixture was stirred for 2 hours. The solvents wereremoved under vacuum, and dissolved in 20% methanol in chloroform. Thesolution was filters and the solvent removed. The residue waschromatographed on silica gel, eluting with 1:1:1:1 n-butanol:ethylacetate:H₂ O:acetic acid to provide 349 mg of title product. MS 275(M+H)⁺ ; ¹ H NMR (D₂ O) δ: 1.44 (s, 9H), 3.03 (m, 1H), 3.30 (m, 1H),3.40 (s, 3H), 3.48 (m, 1H), 3.60 (t, 2H), 3.75 (m, 1H).

Step 312j.(3R,1S)-8-(3-(1-amino-2-hydroxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A 107 mg (0.33 mmol) sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 2.5 mL ofanhydrous acetonitrile, reacted with the compound from step 3 12i above(0.825 mmol), and carded forward as described in Example 253j-1 to give74 mg of the title product. ¹ H NMR (D₆ -DMSO) δ: 0.60 (m, 2H), 0.94 (m,1H), 1.05 (m, 1H), 1.78 (m, 1H), 2.05 (m, 1H), 2.19 (m, 2H), 2.60 (s,3H), 3.57 (m, 1H), 3.73 (m, 3H), 3.92 (m, 1H), 5.41 (m, 1H), 7.91 (s,1H), 9.09 (d, 1H), 13.83 (br s, 1H).

EXAMPLE 313(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A 150 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 2 mL ofanhydrous acetonitrile, reacted with 1-amino-1-methylethyl)pyrrolidine(155 mg, 0.77 mmol, prepared by standard method from the free basedescribed by Hayakawa et al., U.S. Pat. No. 5,098,912, issued Mar. 24,1992), and carded forward as described in Example 253k-1 to give thetitle product. MS (high resolution) found: 388.2047; calc: 388.2036(M+H)⁺ ; ¹ H NMR (D₆ -DMSO) δ:0.60 (m, 2H), 0.94 (m, 1H), 1.07 (m, 1H),1.33 (s, 3H), 1.34 (s, 1H), 2.83 (m, 1H), 2.07 (m, 1H), 2.19 (m, 2H),2.63 (s, 3H), 3.60 (b t, 1H), 3.68 (b t, 1H), 3.81 (m, 1H), 3.93 (m,1H), 7.90 (s, 1H), 8.11 (b s, 1H), 9.08 (d, 1H), 13.83 (b s, 1Calcd forC₂₁ H₂₇ N₃ O₃ FCl.5 H₂ O:C, 55.93; H, 6.71; N, 9.32; Found: C, 56.07; H,6.71; N, 8.95.

EXAMPLE 3148-(3-(1-aminobutyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Step 314a. 4-(BOC-amino)-3-(nitromethyl)-heptanolic acid ethyl ester

Following the procedure of Example 312 step b, substitutingDL-N-BOC-norvaline methyl ester (prepared from norvaline by standardmethods) for the compound of step 312a thereof, and carrying the productforward via the procedures of Example 312 steps c-e, the title compoundwas prepared.

Step 314b. 4-(BOC-amino)-3-(nitromethyl)-heptanol

Repeating the procedure of example 312 step b, substituting4-(BOC-amino)-3-(nitromethyl)-heptanoic acid ethyl ester (1.3 g, 3.91mmol), from step 314a above, for the compound of step 312a thereof, thetitle compound was prepared. MS 291 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ:0.93 (t,3H), 1.45 (s, 9H), 1.48 (m, 5H), 1.77 (m, 1H), 2.53 (m, 1H), 3.79 (m,3H), 4.33 (m, 1H), 4.38 (dd, 1H), 4.49 (dd, 1H).

Step 314c. 4-(BOC-amino)-(nitromethyl)-heptanol, O-mesityl ether

A 610 mg (2.03 mmol) sample of the compound from step 314c above wasdissolved in 2 mL of CH₂ Cl₂, and the solution was cooled to -10° C. Tothis was added dropwise 289 mg (0.195 mL, 2.52 mmol) of methanesulfonylchloride and 319 mg (3.15 mmol) of triethylamine. The solution wasstirred for 2 hours at 0°-10° C. The solution was diluted with CH₂ Cl₂and washed, once with water, once with 5% NaHCO₃, and once with brine.The solvent was dried over MgSO₄ and filtered, and the solvent wasremoved to give 720 mg of the title product as an oil.

Step 314d. 3-(1-(N-BOC-amino)butyl)pyrrolidine

The 720 mg sample of the product from step 314c was dissolved in 50 mLof methanol and hydrogenated over 360 mg of 10% Pd/C catalyst at 4 Atmand room temperature for 24 hours. MS 2243 (M+H)⁺ ; ¹ H NMR (CD₃ OD) 67: (0.94 (t, 3H), 1.34 (m, 3H), 1.44 (s, 9H), 1.48 (m, 1H), 1.70 (m, 1H),2.13 (m, 1H), 2.37 (q, 1H), 3.04 (m, 1H), 3.22 (m, 1H), 6.71 (b d, 1H).

Step 314f.8-(3-(1-aminobutyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A 238 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 5 mL ofanhydrous acetonitrile, reacted with 3-(1-(N-BOC-amino)butyl)pyrrolidine(620 mg, 1.83 mmol, prepared in step 314d above), and carried forward asdescribed in Example 253j-1 to give the title product. MS (highresolution) found: 402.2199; calc: 402.2193 (M+H)⁺ ; ¹ H NMR (D₆ -DMSO)δ:0.60 (m, 2H), 0.89 (m, 4H), 1.05 (m, 1H), 1.49 (m, 5H), 1.17 (m, 1H),2.14 (m, 1H), 2.27 (m, 1H), 2.62 (s, 3H), 3.77 (m, 4H), 3.94 (m, 1H),7.89 (s, 1H), 8.54 (b m, 1H), 9.07 (d, 1H), 11.47 (br, 1H).

EXAMPLES 315-323

Following the procedures of Steps 253j, 253k and 253l above, replacingthe 3-BOC-aminopyrrolidine of Step 253j with the reagent shown, thecompounds of Examples 315-323 are prepared as shown in Table 12, below.

                                      TABLE 12                                    __________________________________________________________________________     ##STR205##                                                                   Ex. No.                                                                            Reagent              R.sup.2                                             __________________________________________________________________________    315                                                                                 ##STR206##                                                                                         ##STR207##                                         316                                                                                 ##STR208##                                                                                         ##STR209##                                         317                                                                                 ##STR210##                                                                                         ##STR211##                                         318                                                                                 ##STR212##                                                                                         ##STR213##                                         319                                                                                 ##STR214##                                                                                         ##STR215##                                         320                                                                                 ##STR216##                                                                                         ##STR217##                                         321                                                                                 ##STR218##                                                                                         ##STR219##                                         322                                                                                 ##STR220##                                                                                         ##STR221##                                         323                                                                                 ##STR222##                                                                                         ##STR223##                                         __________________________________________________________________________

EXAMPLE 3241-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3-aminopyrrolidinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

Step 324a. trans-N-benzyl-4-trifiuoromethyl-3-pyrrolidinecarboxylic acidethyl ester

Trifluoroacetic acid (3 mL, 1N in CH₂ Cl₂) was added to a stirredsolution of trans-ethyl trifluorocrotonate (4.969 g) andN-benzyl-N-methoxymethyl)trimethylsilylamine (7.00 g, prepared accordingto Chem. Pharm. Bull., 33:2762 (1985)) in 30 mL of CH₂ Cl₂ at 0° C., andthe mixture was stirred for 2 hours. After dilution with CH₂ Cl₂, thesolution was washed with satd. NaHCO₃ solution and water, dried overMgSO₄ and concentrated under vacuum to give a pale yellow liquid (8.75g).

Step 324b. trans-N-benzyl-4-trifluoromethyl-3-pyrrolidinecarboxylic acid

A sample (4.739 g) of this liquid was hydrolyzed with 1.98 g of LiOH.H₂O in THF:H₂ O (25 mL, 1.5:1) at 60° C. to give after workup 3.64 g ofthe intermediate as a solid.

Step 324c. trans-1-benzyl-3-(BOC-amino)-4-trifluoromethylpyrolidine

A sample of the intermediate from 324b (3.64 g), diphenylphosphorylazide (3.50 mL), t-butanol (40 mL), triethylamine (2.3 mL) and 40 mL ofdioxane were mixed and heated at reflux under N₂ for 17 hours. Thesolvents were removed under vacuum. The residue was dissolved in CH₂Cl₂, washed with satd. NaHCO₃ solution and water, dried over MgSO₄ andconcentrated under vacuum. The product was purified by chromatography onsilica gel, eluting with 100:5:5 CH₂ Cl₂ :methanol: NH₄ OH to afford1.77 g of the title compound.

Step 324d. trans-3-(BOC-amino)-4-trifiuoromethylpyrrolidine

The compound from step 324c above (1.55 g) was hydrogenated in 50 mL ofmethanol over 0.45 g of 10% Pd/C catalyst under 4 Atm of H₂ for 3.5days. The catalyst was removed by filtration, and the solvent wasremoved to afford the title compound as a white solid (1.09 g).

Step 324e.1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3-aminopyrrolidinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 steps k and l, replacing the3-BOC-aminopyrrolidine of Example 253j with the compound from step 325dabove, the title compound was prepared (97 mg). MS: 414 (M+1)⁺ ; ¹ H NMR(D₆ -DMSO) δ: 0.63 (m, 2H), 1.01 (m, 2H), 2.39 (m, 1H), 2.70 (s, 3H),3.59 (m, 1H), 3.81 (m, 2H), 4.11-4.25 (m, 3H), 8.01 (s, 1H). Anal. Calcdfor C₁₉ H₁₉ N₃ O₃ F₄.HCl.1.25 H₂ O:C, 48.31; H, 4.80; N, 8.90; Found: C,48.45; H, 4.63; N, 8.53.

EXAMPLE 3251-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3-aminomethylpyrrolidinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

Step 325a. trans-1-benzyl-3-(hydroxymethyl)-4-trifluoromethylpyrroidine

A sample of the compound from Example 324 step a above (4.02 g) wasdissolved in 10 mL of THF, then LAH (8.0 mL, 1.0N in THF) was added, andthe solution was stirred for 30 min at room temperature. The reactionwas quenched, and the product was extracted to give 3.36 g of the titleproduct after removal of the solvent.

Step 325b. trans-1-benzyl-3-(aminomethyl)-4-trifluoromethylpyrrolidine

The compound from step 325a above (3.36 g), triphenylphosphine, andphthalimide were dissolved in 50 mL of THF, and DEAD (2.05 mL) was addeddropwise to the above solution at room temperature. The reaction wascomplete almost immediately, and the solvents were removed. The residuewas dissolved in 50 mL of ethanol, 0.65 mL of NH₂ NH₂.H₂ O was added,and the reaction was heated at reflux under N₂ for 3 hours. The solutionwas cooled to room temperature, 5 mL of conc. HCl was added, and themixture was filtered. The filtrate was concentrated, and the residue wasdissolved in 10% HCl and extracted (6×) with CH₂ Cl₂. The aqueous layerwas then adjusted to pH 11 with NaOH and extracted with CH₂ Cl₂, whichwas washed with H₂ O, dried over MgSO₄ and concentrated. The residue wasdissolved in 7:25 H₂ O:methanol, (BOC)₂ O was added, and the reactionstirred at room temperature for 30 min. The methanol was removed undervacuum, and the aqueous residue was extracted with CH₂ Cl₂. The extractwas washed with H₂ O, dried over MgSO₄ and concentrated. The residue waspurified by chromatography on silica gel, eluting with 1:4 ethylacetate:hexane, to give the title compound as a white solid.

Step 325c. trans-3-(BOC-aminomethyl)-4-trifluoromethylpyrrolidine

The compound from step 325b above was hydrogenated according to theprocedure of Example 324 step d to afford the title compound as a whitesolid.

Step 325d.1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3-aminomethylidinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j above, substituting thecompound from step 325c above for the 3-BOC-aminopyrrolidine thereof,and carrying the reaction product forward as in Example 253 steps k andl above, a 77 mg sample of the title product was prepared. MS: 428(M+1)⁺ ; ¹ H NMR (D₆ -DMSO) δ: 0.63 (m, 2H), 1.02 (m, 2H), 2.36 (m, 1H),2.69 (s, 3H), 2.80 (m, 1H), 3.08 (m, 2H), 3.69 (m, 1H), 3.83 (m, 1H),3.94-4.06 (m, 3H), 7.99 (s, 1H), 9.17 (d, 1H, J=10 Hz). Anal. Calcd forC₂₀ H₂₁ N₃ O₃ F₄.HCl.H₂ O: C, 49.85; H, 5.02; N, 8.72; Found: C, 49.86;H, 5.10; N, 8.93.

EXAMPLE 3263(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-norvalylamino)pyrrolidinyl-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 166, replacing the startingpyrido-pyrimidine material thereof with the product of Example 253 stepj, the title compound was prepared. MS: 445 (M+1)⁺ ; Anal. Calcd for C₂₃H₂₉ N₄ O₄ F.1.5HCl.0.75 H₂ O:C, 53.88; H, 6.29; N, 10.93; Found: C,53.87; H, 6.10; N, 11.10.

EXAMPLE 3273(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 167,-replacing the startingpyrido-pyrimidine material thereof with the product of Example 253 stepj, 97 mg of the title compound was prepared. MS: 417 (M+1)⁺ ; ¹ H NMR(D₆ -DMSO) δ:0.60 (m,2H), 1.00 (m, 2H), 1.35 (d, 3H, J=7 Hz), 2.00 (m,1H), 2.20-2.31 (m, 2H), 2.62 (s, 3H), 3.56 (m, 1H), 3.80 (m, 2H),3.93-4.06 (m, 2H), 4.43 (m, 1H), 7.91 (s, 1H), 8.19 (br, 3H), 8.91 (d,1H, J=6 Hz), 9.09 (d, 1H, J=10.5 Hz), 13.85 (br, 1H). Anal. Calcd forC₂₁ H₂₅ N₄ O₄ F.2HCl: C, 51.54; H, 5.56; Found: C, 51.50; H, 5.48.

EXAMPLE 3283(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanyl-(S)-alanylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 168, replacing the startingpyrido-pyrimidine material thereof with the product of Example 253 stepj, 680 mg of the title compound was prepared. MS: 488 (M-Cl)⁺ ; ¹ H NMR(D₆ -DMSO) δ:0.60 (m, 2H), 1.00 (m, 2H), 1.23 (d, 3H, J=7.5 Hz), 1.33(d, 3H, J=7.0 Hz), 1.98 (m, 1H), 3.85-4.01 (m, 4H), 4.314.37 (m, 2H),7.91 (s, 1H), 8.13 (br, 3H), 8.47 (d, 1H, J=6.0 Hz), 8.65 (d, 1H, J=7.5Hz), 9.10 (d, 1H, J=10.5 Hz). Anal. Calcd for C₂₄ H₃₀ N₅ O₅ F.3HCl.0.5H₂ O:C, 46.18; H, 5.57; N, 11.22; Found: C, 46.34; H, 5.77; N, 11.52.

EXAMPLE 3291-cyclopropyl-7-fluoro-6-methyl-4-oxo-8-(3-aminopyrrolidinyl)-4H-quinolizine-3-carboxylicacid hydrochloride

Step 329a.4-t-butoxy-3-chloro-2,5-difluoro-6-(trimethylsilylmethyl)pyridine

To a stirred solution of 4-t-butoxy-3-chloro-trifluoropyridine (7.55 g,prepared as in Example 253 step a above) in 200 mL of THF at -78° C. wasadded trimethylsilylmethyl lithium (1.0M in pentane, 66 mL) dropwise,and the resulting solution was stirred for 1 hour. The reaction wasquenched with satd NaCl solution, and the mixture was extracted withether. The extract was washed with brine, dried over MgSO₄ andconcentrated. The residue was purified by chromatography on silica gel,eluting with 1:32 ethyl acetate: hexane to give 6.26 g of titlecompound.

Step 329b. 4-t-butoxy-2,5-difluoro-6-(trimethylsilylmethyl)pyridine

The compound from step 329a above was dissolved in 100 mL of ethylacetate, and 15 mL of triethylamine and 1.3 g of 10% Pd/C were added.The mixture was shaken under 4 Atm of H₂ for 24 hours. The catalyst wasremoved, and the filtrate was concentrated. The residue was purifiedwith column chromatography on silica gel, eluting with 1:32 ethylacetate:hexane to give 4.38 g of a colorless liquid.

Step 329c. 2,5-difluoro-4-t-butoxy-6-methylpyridine

A 1.00 g sample of the compound from step 329b above was dissolved in 10mL of THF, BH₄ NF (1.0M in THF, 3.7 mL) was added, and the reaction wasstirred at room temperature for 2.5 hours. The solvent was removed, andthe residue was dissolved in ether, which was then washed with water,brine, and dried over MgSO4. Removal of the solvent and purification ofthe residue by chromatography on silica gel, eluting with 1:32 ethylacetate:hexane, gave 0.68 g of the title compound as a colorless liquid.

Step 329d.1-cyclopropyl-7-fluoro-6-methyl-4-oxo-8-(3-aminopyrrolidinyl)-4H-quinolizne-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step e, replacing the3-methylpyridine compound thereof with the 6-methyl compound form step329c above, and carrying the product forward according to steps 253e-l,a 31 mg sample of the title compound was prepared. MS: 346 (M-Cl)⁺ ; ¹ HNMR (D₆ -DMSO) δ: 0.53 (m, 2H), 0.99 (m, 2H), 1.87 (m, 1H), 2.20 (m,1H), 2.34 (m, 1H), 2.87 (d, 3H, J=5.5 Hz), 3.76-4.02 (m, 5H), 6.92 (d,1H), J=9 Hz), 7.72 (s, 1H), 8.38 (br, 3H). Anal. Calcd for C₁₈ H₂₀ N₃ O₃F.HCl.1.5 H₂ O; C, 52.88; H, 5.92; N, 10.28; Found: C, 52.60; H, 5.98;N, 10.18.

EXAMPLE 3301-cyclopropyl-7-fluoro-4H-8-(1-imidazolyl)-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-t-BOC-aminopyrrolidine thereof with imidazole, and carrying theproduct forward as in Example 253 step k, the title compound wasprepared. HRMS: (M+H)⁺ calcd: 328.1097; found: 328.1110 ¹ H NMR (CDCl₃)δ: 0.90 (m, 2H), 1.18 (m, 2H), 2.40 (m, 1H), 2.83 (s, 3H), 7.15 (s, 1H),7.39 (s, 1H), 7.71 (s, 1H), 8.66 (s, 1H), 9.43 (d, 1H, J=6 Hz).

EXAMPLE 3318-(3-amino-1-pyrrolidinyl)-1-ethyl-7-fluoro-4H-4-oxo-9-methyl-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step e, replacing thecyclopropylacetonitrile compound thereof with propionitrile, andcarrying the product forward as in Example 253 steps e-l, the titlecompound was prepared. MS: 334 (M-Cl)⁺ ; ¹ H NMR (D₆ -DMSO) δ:2.28 (m,3H), 2.22 (m, 1H), 2.52 (m, 4H), 2.96 (m, 2H), 3.88-4.18 (m, 5H), 8.01(s, 1H), 9.05 (d, 1H, J=10 Hz). Anal. Calcd for C₁₇ H₂₀ N₃ O₃ FCl.HCl1.5H₂ O:C, 51.45; H, 6.10; N, 10.59; C1, 8.93; Found: C, 51.51; H, 5.90; N,10.78; Cl, 8.91.

EXAMPLE 3328-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-9-ethyl-7-fluoro-4H-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step c, replacing the methyliodide thereof with ethyl iodide, and carrying the product forward as inExample 253 steps 253d-l, the title compound was prepared. MS: 360(M-Cl)⁺ ; ¹ H NMR (D₆ -DMSO) δ:0.52 (m, 2H), 0.87 (t, 3H, J=6 Hz), 0.98(m, 2H), 2.20 (m, 2H), 2.33 (m, 1H), 3.20 (m, 2H), 3.65-3.96 (m, 5H),7.95 (s, 1H), 8.43 (br, 3H), 9.07 (d, 1H, J=10.5 Hz), 13.83 (br, 1H).Anal. Calcd for C₁₉ H₂₂ N₃ O₃ F.1.25 HCl.1.5 H₂ O: C, 53.95; H, 6.01; N,9.93; Found: C, 53.82; H, 5.87; N, 10.18.

EXAMPLE 3331-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(1,2,3-triazol-1-yl)-1-pyrrolidinyl)-quinolizine-3-carboxylicacid

Step 333a. 1-benzyl-3-(1,2,3-triazol-1-yl)pyrrolidine

A solution of 3-azido-1-benzylpyrrolidine (2.30 g) andtrimethylsilylacetylene (8.0 mL) in 15 mL of toluene was heated atreflux for 18 hours. The solvents were removed to give an oily residue.The residue was dissolved in 20% HCl and heated at reflux for 16 hours.The solution was cooled, made basic with NaHCO₃, and extracted withmethylene chloride. The organic layer was washed with water, dried overMgSO₄ and concentrated. The crude product was purified by chromatographyon silica gel, eluting with CH₂ Cl₂ :methanol:NH₄ OH 100:10:1.

Step 333b. 3-(1,2,3-triazol-1-yl)pyrrolidine

The compound from step 333a was dissolved in methanol and hydrolyzed byhydrogenation for 16 hours with a catalyst of 10% Pd/C. The mixture wasfiltered, and the solvent was removed to give 1.00 g of the product.

Step 333c.1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(1,2,3-triazol-1-ylpyrrolidinyl)-quinolizine-3-carboxylicacid

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with the compound from step 333b, andcarrying the product forward as in Example 253 steps j & k, the titlecompound was prepared. mp 183°-186° C. MS: 398 (M-Cl)⁺ ; ¹ H NMR (D₆-DMSO) δ: 0.61 (m, 2H), 0.99 (m, 2H), 2.31 (m, 1H), 2.56 (m, 2H), 2.62(s, 3H), 3.84 (m, 1H), 3.99 (m, 1H), 4.10 (m, 1H), 4.36 (m, 1H), 5.46(m, 1H), 7.80 (s, 1H), 7.92 (s, 1H), 8.32 (s, 1H), 9.11 (d, 1H, J=11Hz). Anal. Calcd for C₂₀ H₂₀ N₅ O₃ F: C, 60.45; H, 5.07; N, 17.62;Found: C, 60.46; H, 5.20; N, 17.63.

EXAMPLE 3341-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(cis-3-amino-4-methyl-1-pyrrolidinyl)-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with cis-3-BOC-amino-4-methylpyrrolidine,and carrying the product forward as in Example 253 steps j-l, the titlecompound was prepared. MS: 360 (M-Cl)⁺ ; ¹ H NMR (D₆ -DMSO) δ:0.60 (m,2H), 0.99 (m, 2H), 1.18 (d, 3H, J=7 Hz), 2.30 (m, 1H), 2.62 (s, 3H),3.48-4.00 (m, 6H), 7.94 (s, 1H), 8.40 (m, 3H), 9.10 (d, 1H, J=10.5 Hz).Anal. Calc C₁₉ H₂₂ N₃ O₃ F.HCl.1.25 H₂ O: C, 54.55; H, 6.14; N, 10.04;Found: C, 54.62; H, 6.10; N 10.08.

EXAMPLE 3358-(2-aminomethyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 2-aminoethylamine, and carrying theproduct forward as in Example 253 steps j-l, the title compound wasprepared. MS: 320 (M-Cl)⁺ ; ¹ H NMR (D₂ O) δ:0.60 (m, 2H), 1.02 (m, 2H),2.02 (m, 1H), 2.64 (s, 3H), 3.40 (m, 2H), 3.99 (m, 2H), 7.40 (s, 1H),8.80 (d, 1H, J=10.5 Hz). Anal. Calcd for C₁₆ H₁₈ N₃ O₃ F.HCl.0.85 H₂ O:C, 51.78; H, 5.62; N, 11.32; Found: C, 51.79; H, 5.31; N, 11.15.

EXAMPLE 3368-(3-(ethylaminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with3-((N-BOC-N-ethyl)amino)methylpyrrolidine, and carrying the productforward as in Example 253 steps j-l, the title compound was prepared.MS: 388 (M-Cl)⁺ ; ¹ H NMR (CD₃ OD) δ:0.60-0.68 (m, 2H), 1.05 (m, 2H),1.37 (m, 3H), 1.91 (m, 1H), 2.31 (m, 2H), 2.68 (s, 3H), 2.69 (m, 1H),3.15 (m, 2H), 3.33 (m, 2H), 3.75-3.96 (m, 4H), 8.01 (s, 1H), 9.03 (d,1H, J=10.5Hz). Anal. Calcd for C₂₁ H₂₆ N₃ O₃ F.1.25 HCl.H₂ O: C, 55.92;H, 6.54; N, 9.32; Found: C, 56.18; H, 6.32; N, 9.27.

EXAMPLE 3378-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-(N-BOC-aminoethyl)pyrrolidine, andcarrying the product forward as in Example 253 steps j-l, the titlecompound was prepared. MS: 374 (M-Cl)⁺ ; Anal. Calcd for C₂₀ H₂₄ N₃ O₃F.HCl.H₂ O: C, 56.14; H, 6.36; Found: C, 56.27; H, 6.14.

EXAMPLE 3381-cyclopropyl-7-fluoro-4H-9-methyl-8-(2-methyl-2,8-diaza-8-bicyclo[4,3,0]nonyl)-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with2-methyl-2,8-diaza-bicyclo[4,3,0]nonane, and carrying the productforward as in Example 253 steps j-l, the title compound was prepared.MS: 400 (M-Cl)⁺ ; ¹ H NMR (DMSO-d₆) δ:0.65 (m, 2H), 0.92 (m, 1H), 1.09(m, 1H), 1.80-1.95 (m, 5H), 2.31 (m, 1H), 2.69 (s, 3H), 2.83 (m, 5H),3.61-4.34 (m, 5H), 7.90 (s, 1H), 9.10 (d, 1H, J=10.5 Hz), Anal. Calcdfor C₂₂ H₂₆ N₃ O₃ F.1.25 HCl.0.5 H₂ O: C, 58.20; H, 6.27; N, 9.25;Found: C 58.09; H, 6.27; N, 9.25.

EXAMPLE 339 1-cyclopropyl-7-fluoro-4 H-8-((1S,4S)-2,5-diaza-bicyclo[2,2,1]heptan-2-yl)-9-methyl-4-oxo-quinolizine-3-carboxlicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with(1S,4S)-2,5-diaza-5-BOC-bicyclo[2,2,1 ]heptane (prepared according to J.Med Chem., 32:1598 (1988)), and carrying the product forward as inExample 253 steps j-l, the title compound was prepared. MS: 358 (M-Cl)⁺; ¹ H NMR (DMSO-d₆) δ:0.59 (m, 1H), 0.93 (m, 1H), 1.06 (m, 1H), 2.05 (m,1H), 2.31 (m, 2H), 2.59 (s, 3H), 3.45 (m, 2H), 3.61 (m, 1H), 4.09 (m,1H), 4.51 (m, 1H), 4.96 (m, 1H), 7.97 (s, 1H), 9.07 (br, 1H), 9.20 (d,1H, J=10.5 Hz), 9.54 (br, 1H). Anal. Calcd for C₁₉ H₂ O: N₃ O₃ F.1.5HCl.1.0 H₂ O: C 53.06; H, 5.51; N, 9.77; Found: C, 53.19; H, 5.37; N,9.58.

EXAMPLE 3401-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(2-pyridinyl)-1-pyrrolidinyl)-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-(2-pyridinyl)pyrrolidine, andcarrying the product forward as in Example 253 steps j-l, the titlecompound was prepared. MS: 408 (M-Cl)⁺ ; ¹ H NMR (DMSO-d₆) δ:0.60 (m,2H), 0.99 (m, 2H), 2.30-2.40 (m, 2H), 2.60 (m, 1H), 2.64 (s, 3H),3.86-4.16 (m, 4H), 7.80 (m, 1H), 7.90 (s, 1H), 9.07 (d, 1H, J=11 Hz).Anal. Calcd for C₂₃ H₂₃ N₃ O₃ F .HCl.H₂ O: C, 55.43; H, 5.26; N, 8.43;Found: C, 55.69; H, 4.97; N, 8.52.

EXAMPLE 3418-((1R*,2S*,6R*)-2-amino-8-azabicyclo[4,3,0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 341a. 1R*,2S*,6R*-2-BOC-amino-8-azabicyclo[4,3,0]nonane

Two mL of 1.0N trifluoracetic acid was added to a stirred solution of2.o mL of cyclohexane and 4.92 g ofN-benzyl-N-(methoxymethyl)-trimethylsilylmethylamine in 20 mL ofmethylene chloride at 0° C. The mixture was stirred at room temperaturefor 16 hours, then diluted with methylene chloride. The solution waswashed with NaHCO₃ and water, then dried over MgSO4. Removal of thesolvent left an oily residue. The residue was dissolved in 65 mL ofmethanol, after which were added 2.2 g of NH₂ OH.HCl, 10 mL of 10% NaOH,and 6.5 mL of methylene chloride, and the reaction was heated at 60° C.for 3 hours. The solvents were removed, and the residue was dissolved inmethylene chloride, which was washed with water, dried over MgSO₄ andconcentrated to give an oil. The oil was dissolved in 50 mL of THF, 1.57g of LAH were added, and the mixture was heated at reflux for 2 hours.The reaction was quenched with water, the solid was removed, and thefiltrate was concentrated. The concentrate was dissolved in 40 mL ofmethanol and 10 mL of water. To this solution was added 5.0 g of (BOC)₂O and the reaction was stirred for 16 hours. The methanol was removedunder vacuum, and the residue was extracted with methylene chloride. Theextract was washed with water, dried over MgSO₄ and concentrated to givean oil. The oil was purified by chromatography on silica gel, elutingwith 100:5:0.5 methylene chloride:methanol:NH₄ OH to give 0.36 g of the1R*,2S*,6R* isomer and 2.22 g of the 1R*,2R*,6R* isomer of the titlecompound. The 1R*,2S*,6R* isomer was stirred with 0.12 g of 10%Pd/C in25 mL of methanol under 4 Atm of H₂ for 48 hours. The catalyst wasfiltered off, and the solvent was removed to give the title compound.

341b.8-((1R*,2S*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with1R*,2S*,6R*-2-BOC-amino-8-azabicyclo[4.3.0]nonane, prepared in step 341aabove, and carrying the product forward as in Example 253 steps j-l, thetitle compound was prepared. MS: 400 (M-Cl)⁺ ; ¹ H NMR (DMSO-d₆) δ: 0.63(m, 2H), 0.94 (m, 1H), 1.05 (m, 1H), 1.42-1.62 (m, 4H), 1.97 (m, 1H),2.31 (m, 2H), 2.62 (s, 3H), 2.67 (m, 1H), 3.19 (m, 1H), 3.54 (m, 1H),3.82 (m, 1H), 4.00 (m, 2H), 7.89 (s, 1H), 8.18 (br, 3H), 9.06 (d, 1H,J=11 Hz). Anal. Calcd for C₂₂ H₂₆ N₃ O₃ F.1.25 HCl.1.5 H₂ O: C, 55.55;H, 6.43; N, 8.83; Found: C, 55.40; H, 6.38; N, 8.72.

EXAMPLE 3428-((1R*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 342a. 1R*,2R*,6R*-2-BOC-amino-8-azabicyclo[4,3,0]nonane

Removing the N-benzyl group from the 1R*,2R*,6R*-isomer of Example 341step a, the title compound was prepared.

Step 341 b.8-((1R*,2R*,6R*)-2-amino-8-azabicyclo[4,3,0]nonan-8-yl))-1-cyclopyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with1R*,2R*,6R*-2-BOC-amino-8-azabicyclo[4.3.0]nonane, prepared in step 342aabove, and carrying the product forward as in Example 253 steps j-l, thetitle compound was prepared. MS: 400 (M-Cl)⁺ ; ¹ H NMR (DMSO-d₆) δ:0.53-0.61 (m, 2H), 0.95-1.06 (m, 2H), 1.30 (m,2H), 1.60 (m, 2H), 1.81(m, 2H), 2.29 (m, 1H), 2.49 (m, 1H), 2.64 (2, 3H), 2.77 (m, 1H),3.32-3.49 (m, 3H), 4.16 (m, 2H), 7.91 (s, 1H), 8.33 (br, 3H), 9.06 (d,1H, J=10 Hz). Anal. Calcd for C₂₂ H₂₆ N₃ O₃ F.1.0 HCl.1.25 H₂ O: C,57.64; H, 6.49; N, 9.17; Found: C, 57.70; H, 6.80; N, 9.18.

EXAMPLE 343 8-((1α,5α,6α)-6-amino-3-azabicyclo[3,1,0]hexan-3-yl))-1-cyclopropyl-9-methyl-7-fluoro-4H-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with1α,2α,6α-2-BOC-amino-8-azabicyclo[4.3.0]hexane, prepared according toU.S. Pat. No. 5,298,629, and carrying the product forward as in Example253 steps j-l, the title compound was prepared. MS: 358 (M-Cl)⁺ ; ¹ HNMR (DMSO-d₆) δ: 0.61 (m, 2H), 1.01 (m, 2H), 2.12 (br s, 2H), 2.33 (m,1H), 2.62 (s, 3H), 3.81 (m, 5H), 7.97 (s, 1H), 8.45 (br s, 3H), 9.11 (d,1H, J=10.5 Hz), 13.83 (br, 1H). Anal. Calcd for C₁₉ H₂₀ N₃ O₃ F.1.5HCl.0.5 H₂ O: C, 54.19; H, 5.39; N, 9.98; Found: C, 54.43; H, 5.28; N,9.87.

EXAMPLE 3448-(trans-3-amino-4-fluoro-1-pyrrolidinyl))-1-cyclopropyl-9-methyl-7-fluoro-4H-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 344a. 1-CBZ-3,4-epoxy-pyrrolidine

1-CBZ-3-pyrroline (20 g) was dissolved in 200 mL of CH₂ Cl₂. MCPBA(50-60% pure, 61.5 g) in 500 mL of CH₂ Cl₂ was added to the abovesolution at 0° C., and the reaction was stirred at 45° C. for 18 hours.The reaction mixture was filtered, and the filtrate was treated withNaHSO₃ (ca. 5 g). The solution was then poured into 1 L of 1N NaOH, themixture was shaken, and the organic phase was separated, washed withwater, dried over MgSO₄ and concentrated. The residue was taken directlyto the next step.

Step 344b. trans-3-azido-1-benzyloxycarboxy-4-hydroxypyrrolidine

The compound from step 344a above was dissolved in 250 mL of acetone.NaN3 (20.16 g) in 200 mL of water was added, and the reaction wasstirred at 60° C. for 18 hours. The reaction mixture was poured intosatd. NaCl solution, and the mixture was extracted (3×) with CH₂ Cl₂.The extract was washed with water, dried over MgSO₄ and concentrated.The residue was purified by column chromatography on silica gel, elutingwith 3% methanol in CH₂ Cl₂ to yield 5.92 g of the product.

Step 344c. trans-azido-1-benzyloxycarboxy-4-fluoropyrrolidine

The compound from step 344b above was dissolved in 15 mL of CH₂ Cl₂ andcooled to -78° C. DAST (0.82 mL) was added, and the reaction was stirredat room temperature for 16 hours. The solvent was removed, the residuedissolved in ethyl acetate, and the solution was washed with satdNaHCO₃, brine, and dried over mgso4. The solvent was removed, and theresidue was purified by column chromatography on silica gel, elutingwith 1% methanol in CH₂ Cl₂ to yield 0.88 g of the tire compound. ¹ HNMR (CDCl₃) δ: 3.62 (m, 4H), 4.22 (br d, 1H, J=11 Hz), 4.99 (br d, 1H,J=51 Hz), 5.16 (s, 2H), 7.36 (m, 5H).

Step 344d. trans-3-(BOC-amino)-4-fluoropyrrolidine

The compound from step 344c was stirred with Raney Ni in methanol under4 Atm H₂ for 9 hours. The catalyst was removed by filtration. Thefiltrate was concentrated, and the residue was treated with (BOC)₂ O andthe reaction was stirred for 16 hours. The methanol was removed undervacuum, and the residue was extracted with methylene chloride. Theextract was washed with water, dried over MgSO₄ and concentrated. Theresidue was purified by chromatography on silica gel, eluting with100:5:0.5 methylene chloride:methanol:NH₄ OH to give the1-benzyloxycarboxy compound. This protecting group was removed byhydrogenolysis over Pd/C under H₂ for 30 min. The catalyst was removed,and the filtrate was concentrated to give the title compound (331 mg).MS: 205 (M-Cl)⁺ ; ¹ H NMR (CDCl₃) δ: 1.46 (s, (H), 2.67 (dd, J=4.5, 12Hz, 1H), 3.04 (ddd, J=4.5, 14, 36 Hz, 1H), 3.18 (dd, J=14, 25 Hz, 1H),3.44 (dd, J=7.5, 12 Hz, 1H), 4.08-4.12 (m, 1H), 4.49 (br s, 1H), 4.98(br d, J=53 Hz, 1H).

Step 344e.8-(trans-3-amino-4-fluoro-1-pyrrolidinyl))-1-cyclopropyl-9-methyl-7-fluoro-4H-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with the compound from step 344d above,and carrying the product forward as in Example 253 steps j-l, the titlecompound (44 mg) was prepared. MS: 354 (M-Cl)⁺ ; HRMS: calc for C₁₈ H₁₉N₃ O₃ F₂ (M₋₋ Cl)⁺ : 354.1473; found: 354.1480. ¹ H NMR (DMSO-d₆) δ:0.62 (m, 2H), 1.00 (m, 2H), 2.35 (m, 1H), 2.58 (s, 3H), 3.77 (m, 1H),3.93 (m, 1H), 4.11 (m, 1H), 4.31-4.41 (m, 1H), 5.50 (br d, J=51 Hz, 1H),7.99 (s, 1H), 8.69 (br s, 3H), 9.16 (d, J=9 Hz, 1H), Anal. Calcd for C₁₈H₁₉ N₃ O₃ F₂.1.3 HCl.2.0 H₂ O C, 48.39; H, 5.48; N, 9.40; Found: C,48.12; H, 5.58; N, 9.53.

EXAMPLE 3451-cyclopropyl-7-fluoro-4H-8-(1-homopiperazinyl))-9-methyl-4-oxo-quinolizine-3-carboxylicacid, acetic acid salt

Following the procedure of Example 298, replacing the3-(dimethylamino)pyrrolidine thereof with the homopiperazine, the titlecompound was prepared. mp 195°-198° C. (dec.). MS: 360 (M+H)⁺ ; ¹ H NMR(DMSO-d₆) δ: 0.55 (m, 2H), 0.98 (m, 2H), 1.83 (s, 6H), 2.26-2.38 (m,2H), 2.69 (br s, 3H), 2.89 (m, 4H), 8.08 (br s, 1H), 9.04 (br s, 1H).

EXAMPLE 3467,9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo-1-phenyl-quinolizine-3-carboxylicacid hydrochloride

Step 346a. 1-(2,3,5,6-tetrafluoro-4-pyridinyl)-4-methylpiperazine

To a cold solution of pentafluoropyridine (16.1 g, 95.2 mmol) andtriethyl amine (11.1 g, 110 mmol) in 150 mL of CH₂ Cl₂ a solution ofN-methylpiperazine (10.0 g, 100 mmol) in 50 mL of CH₂ Cl₂ was addeddropwise. The solution was stirred for 2 hours, then stirred for 16hours at room temperature. The solution was extracted with water andwashed with brine, and the organic layer was dried over MgSO₄ andconcentrated to give 23.25 g of the product. MS: 250 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ: 2.35 (s, 3H), 2.55 (m, 4H), 3.5 (m, 4H).

Step 346b.1-(2-hydrazino-3,5,6-trifluoro-4-pyridinyl)-4-methylpiperazine

To a solution of the compound from step 346a above (23.24 g, 93.2 mmol)in 500 mL of ethanol was added 37.34 g (746 mmol) of hydrazine hydrate,and the reaction was heated at reflux for 16 hours. The solvent wasremoved, and the residue was dissolved in CH₂ Cl₂. The solution waswashed with water, dried over MgSO4, filtered and the solvent removedunder vacuum. The residue was triturated with ether, and collected byfiltration to obtain 17.42 g of light yellow solid. mp 174°-5° C. MS:262 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 2.35 (s, 3H), 2.52 (m, 4H), 3.42 (m,4H), 3.76 (s, 2H), 5.68 (s, 1H). Anal. Calcd for C₁₀ H₁₄ N₅ F₃ : C,45.97; H, 5.40; N, 26.81; Found: C, 45.99; H, 5.34; N, 26.65.

Step 346c. 1-(2.3.5-trifluoro-4-pyridinyl)-4-methylpiperazine

A suspension of 17.36 g (66.4 mmol) of the compound from step 346b abovein 200 mL of ethanol and 20 mL of 20% NaOH was stirred and air wasbubbled through for 16 hours. The mixture was poured into brine, andthis mixture was extracted with CH₂ Cl₂. The extract was dried overMgSO4, filtered, and the solvent was removed to give 13.40 g of a solid.The residue was purified by chromatography on silica gel, eluting withethyl acetate, to afford 11.54 g of pure title product. MS: 232 (M+H)⁺ ;¹ H NMR (CDCl₃) δ:2.34 (s, 3H), 2.52 (m, 4H), 3.46 (m, 4H), 7.66 (m,1H). Anal. Calcd for C₁₀ H₁₂ N₃ F₃ ; C, 51.94; H, 5.23; N, 18.18; Found:C, 51.63; H, 4.92; N, 17.73.

Step 346d.2-(3,5-difluoro-4-(4-methylpiperazinyl)-2-pyridinyl)-phenylacetonitrile

A solution of LDA (99.4 mmol, 66.3 mL, 1M in cyclohexane) in 50 mL ofTHF was prepared and cooled at -78° C. for 15 min. To this solution wasadded in a dropwise manner a solution of 8.87 g (75.7 mmol) ofphenylacetonitrile in 35 mL of THF. The reaction was stirred at -78° C.for 15 min, then 0° C. for 30 min. The solution was then cooled to -60°C. and a solution of the compound from step 346c in 35 mL of THF wasadded dropwise. The reaction mixture was stirred for 1 hour at -60° C.and at 0° C. for 3 hours. The reaction contents were poured into excessNH₄ Cl solution, and the mixture was extracted with CH₂ Cl₂. The extractwas washed with brine, dried over MgSO₄ and filtered, and the solventwas removed. The residue was purified by chromatography on silica gel,eluting with 1:20 methanol:chloroform, to yield 10.24 g of the titlecompound. MS: 329 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ:2.35 (s, 3H), 2.52 (m, 4H),3.41 (m, 4H), 5.43 (s, 1H), 7.35 (m, 3H), 7.45 (m, 2H), 8.13 (m, 1H).Anal. Calcd for C₁₈ H₁₈ N₄ F₂.0.5 H₂ O: C, 64.95; H, 5.57; N, 16.83;Found: C, 62.51; H, 5.50; N, 16.96.

Step 346e. 1-(2-benzyl-3,5-difluoro-4-pyridinyl)-4-methylpiperazine

To a solution of the compound from step 346d above (8.55 g, 26 mmol) in50 mL of ethanol was rapidly added 13.6 mL of conc. H2SO4. After aninitial temperature rise, the solution was stirred at room temperaturefor 2 hr, then at reflux for 48 hours. The reaction solution was cooledand poured into H₂, adjusted to a basic pH with solid K₂ CO₃ andextracted with CH₂ Cl₂. The extract was dried over MgSO₄ and filtered,and the solvent was removed. The residue was purified by chromatographyon silica gel, eluting with ethyl acetate to afford 3.57 g of the titlecompound. MS: 304 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 2.35 (s, 3H), 2.52 (m,4H), 3.40 (m, 4H), 4.07 (m, 2H), 7.20 (m, 1H), 7.30 (m, 4H), 8.05 (m,1H).

Step 346f.4-(3,5-difluoro-4-(4-methylpiperazin-1-yl)-2-pyridinyl)-2-ethoxycarbonyl-4-phenyl-2-butenoicacid ethyl ester

To 30 mL of THF cooled to -60° C. was slowly added 5.8 mL of butyllithium (14.5 mmol, 2.5M in hexane), and the solution was stirred for 10min. To this first solution was added dropwise a solution of 3.52 g (116mmol) of the compound from step 346e above in 15 mL of THF. The reactionmixture was stirred for 10 min, then a solution of 3.4 mL (16.8 mmol) ofdiethyl ethoxymethylenemalonate in 15 mL of THF was added dropwise. Thereaction was stirred for 0.5 hours at -60° C., then for 2 hours at roomtemperature. The reaction solution was poured into a 15% aq. NH₄ Clsolution, and the mixture was extracted with CHCl₃. The extract wasdried over MgSO₄ and filtered, and the solvent was removed. The residuewas purified by chromatography on silica gel, eluting with ethyl acetateto afford 4.09 g of the title compound. MS: 520 (M+H)⁺ ; Anal. Calcd forC₂₇ H₃₅ F₂ N₃ O₅ : C, 62.41; H, 6.79; N, 8.09; Found: C, 62.58; H, 6.63;N, 8.07.

Step 346g.7.9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo-1-phenyl-quinolizine-3-carboyxlicacid ethyl ester

A 3.16 g (6.08 mmol) sample of the compound from step 346f above wasdissolved in 20 mL of DMSO, and the solution was heated at reflux for 1hour. The solution was poured into aq. 5 % NaHCO₃ solution, and themixture was extracted with CHCl₃. The extract was washed with brine,dried over MgSO₄ and filtered, and the solvent was removed. The residue(2.23 g) was purified by chromatography on silica gel, eluting with4:1:0.1 ethyl acetate:ethanol:TEA to yield 681 mg of the title compound.MS: 428 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ:1.40 (m, 3H), 2.40 (m, 2H), 2.58 (m,5H), 3.10 (m, 2H), 4.38 (m, 2H), 7.40 (m, 6H), 8.12 (s, 1H), 9.30 (m,1H).

Step 346h.7,9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo-1-phenyl-quinolizine-3-carboxylicacid hydrochloride

A solution of the compound from step 346g above (623 mg, 1.46 mmol) in30 mL of THF was diluted with 15 mL of water. The suspension was cooledin an ice bath for 15 min, then LiOH.H₂ O (183 mg, 4.37 mmol) was added,the reaction was stirred for 1 hour with cooling, then for 16 hours atroom temperature. TLC showed the reaction to be incomplete, so anadditional 123 mg of LiOH.H₂ O was added, and the reaction was stirredfor 24 hours. The reaction contents were poured into H₂ O, and 1.3 mL ofacetic acid were added. Solid NaHCO₃ was added until the solution wasbasic, and the mixture was extracted with CHCl₃ containing a smallamount of DMF. The extract was dried over MgSO₄ and filtered, and thesolvent was removed. Excess DMF was removed by co-distillation withtoluene. The residue was suspended in water and carefully acidified with0.5M HCl. The solution was frozen, and the water removed byfreeze-drying. The solid was triturated with ether, collected byfiltration, and dried for 48 hours at 50° C. in vacuum to yield 171 mgof the title compound. mp 230° C. (dec.). MS: 400 (M+H)⁺ ; ¹ H NMR(DMSO-d₆) δ:2.73 (m, 3H), 2.80 (m, 4H), 3.70 (m, 4H), 7.40 (m, 6H), 7.93(m, 1H), 9.33 (m, 1H), 11.0 (m, 1H). Anal. Calcd for C₂₁ H₂₀ N₃ O₃ F₂.H₂O: C, 55.57; H, 4.89; N, 9.26; Found: C, 55.89; H, 4.62; N, 8.99.

EXAMPLE 347 Scaled-Up Preparation of8-(3(S)-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 347a. 4-t-butoxy-3-chloro-2,5,6-trifluoropyridine

A 927.55 g (5.0 mol) sample of 3-chloro-2,4,5,6-tetrafluoropyridine(from Fluorochem Ltd.) was dissolved in 4 L of anhydrous THF, and thesolution was cooled to -10° C. To this solution was added 429 (5.36 mol)of lithium t-butoxide in portions over a 1-hr period, while maintainingthe temperature between -5° C. to -10° C. The reaction was stirred for 2hours at -10° C., the cooling bath was removed, and the solution waswarmed to room temperature over a 3 hours period. The THF was removedunder reduced pressure. The residue was dissolved in 6 L of ether, andthe solution was washed with 4×1 L of water. The ether solution wasdried over MgSO4, and the ether was removed under reduced pressure togive 1123.44 g of the crude product. The crude product was purified bychromatography, eluting with hexane. bp 43°-47° C./0.6 mm Hg.

Step 347b. 4-t-butoxy-3-methyl-2,5,6-trifluoropyridine

A 499 g (2.08 mol) sample of the compound from step 347a above wasdissolved in 4 L of THF and cooled to -70° C. While maintaining a N₂atmosphere, 1.6 L of sec-butylithium (2.08 mol, 1.3M) was added, and thereaction mixture was stirred for 1 hour. Iodomethane (129.6 mL, 2.08mol) was added rapidly dropwise, while maintaining the temperature below-50° C. The mixture was stirred while allowing the temperature to rise,and the stirring was continued for 16 hours. The reaction was quenchedwith 1 L of water while cooling with an ice bath, then 2 L of hexanewere added, the phases mixed well, and the layers separated. The organiclayer was concentrated on a rotary evaporator. The residue was dissolvedin hexane, dried over MgSO4, filtered and concentrated to give 496 g oftitle compound, which was taken directly to the next step.

Step 347c. 4-t-butoxy-2,5-difluoro-3-methylpyridine

Lithium aluminum hydride (56.7 g, 1.42 mol) was added to 6 L of THF, andthe suspension was stirred under N₂. The temperature was adjusted to 0°to -5° C., and 476.5 g (2.27 mol) of the compound from step 347b above(dissolved in 750 mL of THF) was added in a stream over a 15 min period.The mixture was stirred at room temperature for 16 hours, then 500 mL ofhexane was added. The reaction was then quenched while maintaining aninternal temperature of 10°-20° C. by adding 57 mL of H₂ O, 57 mL of 15%NaOH solution, and 171 mL of H₂ O, in that order. The mixture wasfiltered, and the filter cake was washed with THF and hexane. Thefiltrate was concentrated on a rotary evaporator with a bath temperatureof 35° C. The residue was purified by column chromatography on silicagel, eluting with hexane and 5% ethyl acetate in hexane to afford 141 gof the title compound. Distillation at 80°-90° C. and 1 mm Hg gave 103.4g of the pure product.

Step 347d. Alternate preparation of4-t-butoxy-2,5-difluoro-3-methylpyridine

A 476.5 g (2.27 mmol) sample of the compound from step 347b above wasdissolve in 6 L of THF and stirred under N₂. The temperature of thesolution was adjusted to 0° to 5° C., and a solution of sodiumbis-(2-methoxyethoxy)aluminum hydride in toluene (750 mL, 3.4M, 2.5 mol)was added rapidly dropwise over 1 hour. The reaction mixture was stirredat room temperature for 16 hours, and 500 mL of hexane was added. Thereaction was then quenched while maintaining an internal temperature of<25° C. by careful addition of 500 mL of H₂ O. The organic layer wasdecanted, and the solids were washed thoroughly with hexane. Thesolvents were combined and concentrated on a rotary evaporator, with abath temperature of 55° C. The 440 g of crude product was twice purifiedby chromatography over silica gel, eluting with hexane and 3% ethylacetate in hexane to give 137.5 of the pure title compound.

Step 347e.2-(4-t-butoxy-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile

Diisopropylamine (445 mL, 3.18 mol) was dissolved in 1.5 L of anhydrousTHF and stirred under N₂. The solution was cooled to -40° C., andn-butyllithium (1.274 L, 3.18 mole, 2.5M in hexane) was added at a ratesuch that the internal temperature was maintained at -40° to -20° C. Thesolution was warmed to -10° C., then cooled to -70° C.Cyclopropylacetonitrile (257 g, 3.17 mmol) was added dropwise tomaintain the temperature below -68° C., then the solution was stirredfor 35 min. A sample of 4-t-butoxy-2,5-difluoro-3-methylpyridine, fromstep 347c or 347d above, was dissolved in 1.2 L of anhydrous THF. Tothis solution was added in a dropwise manner the first solutioncontaining the lithium salt of cyclopropylacetonitrile, at a rate thatthe internal temperature remained below -70° C. The solution was stirredat -78° C. for 1 hour, then allowed to warm to 0° C. The reaction wasquenched by adding 1 L of satd aq. NH₄ Cl solution and 1L of H₂ O. Theorganic layer was separated. The aqueous layer was extracted with ethylacetate. The organic layers were combined, washed with brine, dried withMgSO4, and concentrated on a rotary evaporator to give an oil residue.The oil was distilled at 0.2 mm Hg at 25°-35° C. to remove low boilingimpurities and residual cyclopropylacetonitrile. The residue was twicechromatographed on silica gel, eluting with 7% ethyl acetate in hexaneto afford 646 g of pure title compound. MS: 263 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ: 0.50 (m, 2H), 0.64 (m, 1H), 0.75 (m, 1H), 1.43 (d, J=1.5 Hz, 9H),1.50 (m, 1H), 2.29 (s, 3H), 3.76 (d, J=7.5 Hz, 1H), 8.31 (s, 1H).

Step 347f.2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile

To a cooled (0° C.) solution of the compound from step 347e above(189.78 g, 0.72 mol) in 1.6 L of CH₂ Cl₂ and 270 mL of DMF was added 300mL (3.2 mol) of POCl₃, and the reaction was stirred for 12 hours.Another 25 mL (0.27 mol) of POCl₃ was added, and the reaction stirredfor an additional 12 hours. The reaction mixture was then poured into H₂O, and this mixture was stirred for 1 hour. The organic material wasextracted with CH₂ Cl₂, which was washed with H₂ O, sat aq NaHCO₃solution, H₂ O, dried over MgSO4, filtered and evaporated under vacuumto afford 129.3 g of the title compound as an oil. MS: 225,227 (M+H)⁺,191. ¹ H NMR (CDCl₃) δ:0.48 (m, 1H), 0.58 (m, 1H), 0.66 (m, 1H), 0.77(m, 1H), 1.50 (m, 1H), 2.49 (s, 3H), 3.80 (d, J=8 Hz, 1H), 8.39 (s, 1H).

Step 347g.2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetic acid,ethyl ester

To 1 L of ethanol saturated with ca. 400 g HCl gas and stirred under N₂and cooled to 0° C. was added a solution of 135.8 (0.6 mol) of thecompound from step 347f in 90 mL of ethanol, and the reaction wasstirred for 3 hours at 0° C. To this solution was added 90 mL of H₂ O,and the reaction mixture was heated at 80° C. for 2 hours. The mixturewas poured over ice to make a total volume of 4 L. The solution wasneutralized with 50% NaOH to pH 8 while maintaining the temperaturebelow 0° C. The solid was filtered off, redissolved in CH₂ Cl₂, and theresidual water layer removed. The organic layer was dried over MgSO₄ andevaporated to leave a tan solid (134.4 g). MS: 272 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ:0.12 (m, 1H), 0.38 (m, 1H), 0.54 (m, 1H), 0.75 (m, 1H), 1.20(t, J=7.5 Hz, 3H), 1.68 (m, 1H), 2.40 (s, 3H), 3.24 (d, J=9.3 Hz, 1H),4.16 (q, J=7.5 Hz, 2H), 8.36 (s, 1H).

Step 347h.2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylethanol

A solution of the compound from step 347g above (130.72 g, 0.48 mol) in530 mL of anhydrous THF was stirred under N₂ at -78° C. To this wasadded a solution of LiAlH₄ (480 mL, 1M in THF, 0.48 mol) dropwise whilemaintaining the temperature below -60° C. The reaction was stirred at-78° C. for 2 hours. The reaction was quenched by addition of H₂ O (16mL), 15% NaOH (16 mL and H₂ O (46 mL), and the mixture was stirred for 1hour at room temperature. The solid was removed by filtration and washedwith ether. The combined organic were washed with brine, dried overMgSO4, filtered and evaporated under vacuum to afford the title compound(108.6 g) as a white solid. MS: 230 (M+H)⁺, 196; ¹ H NMR (CDCl₃) δ: 0.21(m, 2H), 0.44 (m, 1H), 0.60 (m, 1H), 1.21 (m, 1H), 2.39 (s, 3H), 2.56(m, 1H), 3.52 (br s, 1H), 4.02 (m, 2H), 8.31 (s, 1H).

Step 347i.2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde

Anhydrous DMSO (80 mL, 1.14 mol) was dissolved in 900 mL of anhydrousCH₂ Cl₂, and stirred under N₂. The solution was cooled to -78° C., and asolution of oxalyl chloride (2.0M, 284 mL, 0.569 mol) in CH₂ Cl₂ wasadded over a 20 min period while holding the internal temperature below-60° C. and stirred for 35 min longer. The compound from step 346h (109g, 0.475 mol) was dissolved in 400 mL of anhydrous CH₂ Cl₂ and addeddropwise to the first solution, while holding the internal temperaturebelow -60° C. The reaction mixture was stirred for 30 min, andtriethylamine (327 mL, 2.34 mol) was added dropwise over 10 min. Thereaction was stirred as the internal temperature was raised to -10° C.The reaction was quenched with 500 mL of H₂ O, and the organic layer wasisolated, washed with H₂ O, dried over MgSO₄ and evaporated to give109.64 g of the title compound. MS: 228 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ:0.24(m, 1H), 0.35 (m, 1H), 0.59 (s, 1H), 0.76 (m, 1H), 1.55 (m, 1H), 2.38(s, 3H), 3.19 (dd, J=2.7, 9 Hz, 1H), 8.37 (s, 1H), 9.87 (d, J=2.7 Hz,1H).

Step 347j.4-(4-Chloro-5-fluoro-3-methyl-2-pyridinyl)-4-cyclopropyl-2-ethoxycarbonyl-2-butenoicacid ethyl ester

The compound from step 347i above (109.68 g, 0.48 mol) was dissolved in1.3 L of absolute ethanol and stirred under N₂. To this solution wasadded diethylmalonate (35 1 mL, 2.31 mol), piperidine (45.5 mL, 0.46mol) and acetic acid (45.5 mL, 0.79 mol). The solution was heated atreflux for 8 hours and cooled to room temperature. The solvent wasremoved with a rotary evaporator, and the residue was dissolved in ethylacetate. This solution was washed with water, brine, dried over MgSO₄and concentrated to give an oily residue. The residue was distilled in ashort-path distillation apparatus at 0.2 mm Hg and 25°-56° C. to removeexcess diethyl malonate and volatile impurities. The residual oil wastaken directly to the next step.

Step 347k.8-chloro-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid, ethyl ester

The compound from step 347j above was dissolved in 400 mL of anhydrousDMSO and heated at reflux for 1 hour. The hot reaction mixture wasslowly poured into rapidly stirred ice water (3 L). The product wasfiltered off and washed with water (3 L) and hexane (1.5 L). The productwas dried in a vacuum oven for 16 hours to afford 105 g of the titlecompound as a yellow crystalline solid. MS: 324 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ:0.75 (m, 2H), 1.06 (m, 2H), 1.43 (t, 3H), 2.32 (m, 1H), 3.09 (s, 3H),4.43 (q, 2H), 8.39 (s, 1H), 9.43 (dd, J=l, 6 Hz, 1H).

Step 347l.8-(3(S)-(BOC-amino)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid, ethyl ester

A 93.1 g (0.29 mmol) sample of the compound from step 347k above wasdissolved in 1.24 L of acetonitrile, and 137 g (0.72 mol) of3(S)-(BOC-amino)pyrrolidine and 113 g (1.45 mol) of NaHCO₃ were added.The mixture was heated at reflux under N₂ for 1 hour. The reactionmixture was cooled to 25° C., and 700 mL of H₂ O were added. The mixturewas extracted with ethyl acetate, and the solvent was washed with water,1N HCl, water and brine. The solvent was dried over MgSO₄ andconcentrated to a thick tar. MS: 474 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 0.60(m, 2H)0.95 (m, 2H), 1.41 (t, 3H), 1.42 (m, 2H), 1.46 (s, 9H), 2.60 (s,3H), 3.50 (m, 1H), 3.82 (m, 1H), 3.95 (m, 1H), 4.49 (q, 2H), 4.79 (br s,1H), 8.2 (s, 1H), 9.25 (d, 1H).

Step 347m.8-(3(S)-(BOC-amino)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

The material from step 347l above was dissolved in 900 mL of THF, and550 mL of water and 107.5 g (2.56 mol) of LiOH.H₂ O were added. Themixture was heated at reflux under N₂ for 1 hour. The mixture wasdiluted by pouting into a mixture of 1 L of THF and 0.5 L of water, withaddition of ice to assist cooling. Conc. HCl was added with vigorousmixing to bring the acidity to pH 4, while holding the internaltemperature below 15° C. The yellow precipitate was filtered off, thendissolved in CH₂ Cl₂. The solution was washed with water until thewashings tested neutral, then dried over MgSO₄ and concentrated. MS: 446(M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 0.69 (m, 2H), 1.02 (m, 2H), 1.48 (s, 9H),2.12 (m, 2H), 2.30 (m, 1H), 2.62 (s, 3H), 3.60 (m, 1H), 3.79 (m, 1H),3.96 (m, 2H), 4.38 (br s, 1H), 5.11 (br s, 1H), 8.13 (s, 1H), 8.99 (d,1H), 13.82 (s, 1H).

Step 347n.8-(3(S)-amino)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

A 140 g sample of the compound from step 347m above was dissolved in 1.2L of CH₂ Cl₂, and 1.0 L of 1.0M HCl in acetic acid was added over 5 min.The mixture was stirred under N₂ for 1 hour at room temperature. Theproduct was collected by filtration and washed with CH₂ Cl₂ untilcolorless. The solid was dried in a vacuum oven (50° C., 10 mm Hg) for48 hours. This material (307.45 g) was added to 3.8 L of absoluteethanol prewarmed to 70° C. To the mixture was added 1.23 L of H₂ O, andthe mixture was heated to boiling and stirred until all solid dissolved.Stirring was discontinued, seed crystals were added, and the solutionallowed to cool to room temperature. The mixture was then cooled at 0°C. for 12 hours and at -25° C. with stirring for 2 hours. The productwas filtered off and washed with chilled absolute ethanol. The solid wasdried in vacuum for 48 hours to give the title product (261 g) as ayellow solid. MS: 346 (M-Cl)⁺ ; ¹ H NMR (CD₃ OD) δ: 0.69 (m, 2H), 1.06(m, 2H), 2.26 (m, 2H), 2.52 (m, 1H), 2.73 (s, 3H), 3.88 (m, 2H), 4.05(:m, 2H), 4.18 (m, 1H), 4.88 (br s, 1H), 8.03 (s, 1H), 9.02 (d, J=10.8Hz, 1H).

EXAMPLE 3488-(spiro-1,3-dioxacyclopentane[2,3]-1-piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Step 348a. N-CBZ-3-hydroxypiperidine

A sample of 3-hydroxypiperidine HCl (50.0 g) was dissolved in a smallamount of water and the solution was cooled to 0° C. in an ice bath. TheHCL was neutralized by slow addition of 363 mL of 1M NaOH. An additional1.2 eq of 1 M NaOH was added quickly, and 52 mL of benzyl chloroformatein 20 mL of ether was added dropwise, then the solution was stirred for4 hours at 0° C. The solution was diluted with 600 mL of water andextracted with methylene chloride. The organic extract was dried overNa₂ SO₄, filtered, and taken to dryness to afford 89.2 g of the titlecompound.

Step 348b. N-CBZ-3-oxo-piperidine

A 30.0 g sample of N-CBZ-3-hydroxypiperidine, from step 348a above, wasdissolved in 250 mL of DMSO, and the solution was cooled to 0° C. Tothis solution, stirred at 0°, was added 142 mL of diethylamine, and nextwas added dropwise a solution of 60.88 g of pyridine.SO₃ complexdissolved in 250 mL of DMSO. The cooling bath was removed, and thereaction mixture was stirred at room temperature for 20 hours. Thereaction mixture was diluted with water, and the mixture was extractedwith methylene chloride. The extract was dried over Na₂ SO₄, filtered,and taken to dryness. The DMSO was distilled off under reduced pressure,and the residue purified by distillation in a kugelrohr apparatus toyield 26.53 g of the title compound.

Step 348c. spiro-1,3-dioxacyclopentane[2,3]piperidine

A 10.0 g sample of N-CBZ-3-oxo-piperidine, from step 348b above, wasdissolved in 10 mL of toluene and 5.98 mL of ethylene glycol and 0.408 gof p-toluenesulfonic acid were added. The solution was stirred at 130°C. for 96 hours, then poured into 5% NaHCO3 solution. The mixture wasextracted with methylene chloride, the extract was dried over Na₂ SO₄,then the solvent was removed under vacuum and the residue was distilledin a kugelrohr apparatus to give 7.30 g of the title compound.

Step 348d.8-(spiro-1,3-dioxacyclopentane[2,3]-1-piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-yl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof withspiro-1,3-dioxacyclopentane[2.3]piperidine, from step 348c above, andcarrying the product forward as in Example 253 steps j-k, the titlecompound was prepared (245 mg). mp 184°-187° C. MS: 403 (M+1)⁺ ; ¹ H NMR(CDCl₃) δ: 0.69 (m, 2H), 1.03 (m, 2H), 1.88 (m, 2H), 1.99 (m, 2H), 2.28(m, 1H), 2.82 (s, 3H), 3.35 (m, 4H), 3.97 (m, 4H), 8.36 (s, 1H), 9.20(d, 1H, J=3 Hz), 13.91 (s, 1H). Anal. Calcd for C₂₁ H₂₃ N₂ O₅ F.0.5 H₂O: C, 61.31; H, 5.88; N, 6.81; Found: C, 61.41; H, 5.91; N, 6.62.

EXAMPLE 3498-(3-amino-4-methoxypyrrolidinyl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 349a. N-CBZ-pyrroline

A 50.0 g sample of pyrroline (Aldrich) was dissolved in 868 mL of 1MNaOH, and the solution was cooled to 0° C. Benzyl chloroformate (103.29mL) was dissolved in 100 mL of ether and added to the solution ofpyrroline dropwise over a 1 hour period. The solution was stirred for 4hours at 0° C., then diluted with 500 mL of water and extracted withmethylene chloride. The extracts were combined, dried of Na₂ SO₄,filtered, and evaporated to dryness to yield 144.6 g of the titlecompound.

Step 349b. N-CBZ-3,4-epoxy-pyrrolidine

In a dry system under N₂ a 15.0 g sample of N-CBZ-pyrroline, from step349a above, was dissolved in 200 mL of methylene chloride, and thesolution was cooled to 0° C. To this solution was added 46.3 g ofm-chloroperbenzoic acid dissolved in 500 mL of methylene chloridedropwise over a 1 hour period. The reaction mixture was then heated at45° C. for 18 hours, then recooled to 0° C. To the cool solution wasadded 3 g of sodium bisulfite, and the mixture was stirred for 1 hourand poured into 1 L of 1N NaOH. The organic layer was washed with water,dried over Na₂ SO₄, filtered and evaporated to afford 14.5 g of thetitle compound.

Step 349C. N-CBZ-3-azido-4-hydroxy-pyrrolidine

A 16.18 g sample of N-CBZ-3,4-epoxy-pyrrolidine was dissolved in 145 mLof acetone. A 14.39 g sample of sodium azide was dissolved in 130 mL ofwater and added to the acetone solution. The reaction mixture wasstirred at 60° C. for 16 hours, then poured into 400 mL of satd. NaClsolution. The quenched reaction mixture was extracted with methylenechloride, which was dried over Na₂ SO₄, filtered and evaporated. Theresidue was purified by flash chromatography over silica gel to afford21.40 g of the title compound.

Step 349d. N-CBZ-3-azido-4-methoxy-pyrrolidine

A 3.36 g sample of Nail was suspended in 60 mL of THF in a dry flaskunder N₂ and cooled to 0° C. A 20.0 g sample ofN-CBZ-3-azido-4-hydroxy-pyrrolidine, from step 349c above, was dissolvedin 200 mL of THF, and this solution was added dropwise to the suspensionof NaH. The reaction mixture was stirred for 30 min at 0° C., 30 min atroom temperature, and recooled to 0° C. To this solution was addeddropwise a solution of 5.70 mL of methyl iodide in 60 mL of THF. Thereaction mixture was stirred at 0° C. for 30 min and at room temperaturefor 23.5 hours. The reaction mixture was poured into 500 mL of 5% NH₄ Clsolution, and the mixture was extracted with methylene chloride. Theextract was dried over Na₂ SO₄, filtered and evaporated. The residue waspurified by flash chromatography over silica gel to afford 8.99 g of thetitle compound.

Step 349e. N-CBZ-3-amino-4-methoxy-pyrrolidine

A 8.98 g sample of N-CBZ-3-azido-4-methoxy-pyrrolidine, from step 349dabove, was dissolved in 100 mL of methanol and hydrogenated at roomtemperature under 4 Atm of H₂ in the presence of 6.8 g of RaNi for 4days in a sealed bomb. The catalyst was removed by filtration, and themethanol was evaporated. The residue was dissolved in methylenechloride, dried over Na₂ SO₄, and filtered. The solvent was removed toyield 5.60 g of the title compound.

Step 349f. N-CBZ-3-(BOC-amino)-4-methoxy-pyrrolidine

A 5.60 g sample of N-CBZ-3-(BOC-amino)-4-methoxy-pyrrolidine wasdissolved in 120 mL of methylene chloride in a dry flask under N₂ andcooled to 0° C. To this were added 6.61 mL of triethylamine and 7.76 gof di-t-butyl dicarbonate dissolved in 50 mL of methylene chloride(dropwise). The reaction mixture was stirred at )° C. fro 1 hour and atroom temperature for 24 hours. The reaction was quenched by addition towater. The mixture was extracted with methylene chloride. The extractwas dried over Na₂ SO₄, filtered and evaporated to yield 6.88 g of crudeproduct. The residue was purified by flash chromatography over silicagel to afford 1.97 g of pure title compound.

Step 349g. 3-(BOC-amino)-4-methoxy-pyrrolidine

A 1.97 g sample of N-CBZ-3-(BOC-amino)-4-methoxy-pyrrolidine, from step349f above, was hydrogenated over 0.2 g of 10% Pd/C in 100 mL ofmethanol under 4 Atm of H₂ at room temperature for 24 hours. Thecatalyst was removed by filtration, the solvent was removed to yield1.28 g of title compound.

Step 349h.8-(3-amino-4-methoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-(BOC-amino)-4-methoxypyrrolidine,from step 349g above, and carrying the product forward as in Example 253steps j-l, the title compound was prepared (369 mg). MS: 376 (M+1)⁺ ; ¹H NMR (CD₃ OD) δ: 0.71 (m, 2H), 1.88 (m, 2H), 2.30 (m, 1H), 2.74 (s,3H), 3.51 (s, 3H), 3.84 (m, 2H), 3.98 (m, 1H), 4.24 (m, 3H), 8.02 (s,1H), 9.02 (d, 1H, J=3.5 Hz). Anal. Calcd for C₁₉ H₂₃ N₃ O₄ ClF.4 H₂ O:C, 46.16; H, 6.46; N, 8.68; Found: C, 47.53; H, 6.06; N, 9.36.

EXAMPLE 3508-(4-amino-4-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 350a. N-CBZ-4-hydroxypiperidine

A 35.43 g of 4-hydroxypiperidine was suspended in 420 mL of 1M NaOH, andcooled to 0° C. To this stirred solution was added 50.0 mL of benzylchloroformate dissolved in 100 mL of ether dropwise over a 1 hourperiod. The reaction mixture was stirred for 3 hours, diluted with 200mL of water, and extracted with methylene chloride. The extract wasdried over Na₂ SO₄, filtered and evaporated to afford the titlecompound.

Step 350b. N-CBZ-4-oxopipyridine

A 43.1 g sample of N-CBZ-4-hydroxypiperidine, from step 350a above, wasdissolved in 370 mL of DMSO in a dry flask under N₂ and cooled to 0° C.To this solution was added 204 mL of triethyl amine, then a solution of87.5 g of pyridine.SO₃ in 370 mL of DMSO was added dropwise over aperiod of 1 hour. The reaction was stirred for 24 hours at roomtemperature, then quenched by addition to 1 L of NaCl solution. Themixture was extracted with methylene chloride. The extract was driedover Na₂ SO₄, filtered and evaporated. The residue was chromatographedof a silica gel column to afford 11.49 g of the title compound.

Step 350c. N-CBZ-4-hydroxy-4-methylpiperidine

A 58 mL sample of methyl magnesium bromide was placed into a dry flaskunder N₂ containing 450 mL of dry ether cooled to -20° C. A 25.00 gsample of N-CBZ-4-oxopiperidine, from step 350b above, was dissolved in100 mL of dry ether and added to the reaction vessel dropwise over a 1hour period. The reaction mixture was stirred for 1 hour, then warmed toroom temperature over a 2.5-hour period. The reaction was quenched bydropwise addition of an excess of satd NH₄ Cl solution. The layers wereseparated, and the aqueous layer was extracted with ether. The organiclayers were combined, dried over Na₂ SO₄, filtered and evaporated. Theresidue was distilled in a kugelrohr apparatus to yield 44.3 g of thetitle compound.

Step 350d. N-CBZ-4-(acetylamino)-4-methylpiperidine

A solution of 270 mL of 90% sulfuric acid and 34 mL of acetonitrile wasprepared and cooled to 0° C. A 44.3 g sample ofN-CBZ-4-hydroxy-4-methylpiperidine, from step 350c above, dissolved inacetonitrile was added dropwise to the stirred solution in the reactionvessel over a 2 hours period. The reaction mixture was stirred anadditional 45 min at 0° C. and 2.5 hours without cooling. The reactionmixture was poured over 1 kg of ice, and the mixture was adjusted to pH12-13 with 50% NaOH. This mixture was extracted with ethyl acetate. Theorganic layers were combined, dried over Na₂ SO₄, filtered andevaporated to give the title compound (10 1.5 g) as a white solid.

Step 3.50e. N-CBZ-4-amino-4-methylpiperidine

A 53 g sample of N-CBZ-4-(acetylamino)-4-methylpiperidine, from step350e above, was dissolved in 202 mL of 12M HCl and heated at 115° C. for90 hours. The reaction mixture was poured over 800 g of ice. Thismixture was extracted with methylene chloride. The organic layers werecombined, dried over Na₂ SO₄, filtered and evaporated to give 37.6 g ofthe title compound.

Step 350f. N-CBZ-4-(BOC-amino)-4-methylpiperidine

In a dry flask under N₂ a 37.6 g sample ofN-CBZ-4-amino-4-methylpiperidine, from step 350e above, was dissolved in220 mL of CCl4, 51.3 mL of triethylamine was added, and 52.2 g ofdi-t-butyl dicarbonate was added in small portions. The solution wasstirred at 38° C. for 20 hours, then washed with water. The organicsolvent was dried over Na₂ SO₄, filtered and evaporated to give 23.71 gof title compound.

Step 350g. 4-(BOC-amino)-4-methylpiperidine

A 23.71 g sample of N-CBZ-4-(BOC-amino)-4-methylpiperidine, from step350f above, was hydrogenated as described in Example 349g above to give15.7 g of title compound.

350h.8-(4-amino-4-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 4-(BOC-amino)-4-methylpyrrolidine(Aldrich) and carrying the product forward as in Example 253 steps j-l,the title compound was prepared (513 mg). mp 205°-207° C. MS: 374 (M+1)⁺; ¹ H NMR (CD₃ OD) δ:0.71 (m, 2H), 1.08 (m, 2H), 1.54 (s, 3H), 2.00 (m,4H), 2.38 (m, 1H), 2.87 (s, 3H), 3.60 (m, 4H), 8.20 (s, 1H), 9.27 (d,1H, J=3 Hz. Anal. Calcd for C₂₀ H₂₅ N₃ O₃ ClF.3 H₂ O: C, 51.78; H, 6.73;N, 9.06; Found: C, 51.64; H, 6.39; N, 9.01.

EXAMPLE 3518-(4-(2-hydroxyethyl)piperidinyl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 1-piperidineethanol, obtained fromAldrich, and carrying the product forward as in Example 253 steps j-k,the title compound was prepared (270 mg). MS: 389 (M+1)⁺ ; ¹ H NMR (CD₃OD) δ: 0.73 (m, 2H), 1.09 (m, 2H), 2.40 (m, 1H), 2.93 (s, 3H), 3.42 (m,4H), 3.54 (m, 1H), 3.75 (m, 2H), 3.78 (m, 4H), 3.96 (m, 2H), 8.29 (s,1H), 9.32 (d, 1H), J=3.3). Anal. Calcd for C₂₀ H₂₄ N₃ O₄ F.2.5 H₂ O: C,55.29; H, 6.73; N, 9.67; Found: C, 55.08; H, 6.02; N, 9.56.

EXAMPLE 3528-(4-(methoxymethyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Step 352a. N-CBZ-4-methoxymethoxypiperidine.

A 4.00 g sample of N-CBZ-4-hydroxypiperidine, prepared as in Example350a above, was dissolved in 45 mL of methylene chloride, and 11.85 mLof diisopropylethylamine was added. To this solution was then added 3.87mL of chloromethyl methyl ether dropwise over 10 min. The reactionmixture was stirred at room temperature for 17 hours, diluted with 50 mLof methylene chloride, and washed with 0.5M phosphoric acid, 5% NaHCO₃and water. The solvent was dried over Na₂ SO₄, filtered and evaporatedto give 4.43 g of the title compound.

Step 352b. 4-methoxymethoxypiperidine

A 4.43 g sample of N-CBZ-4-methoxymethoxypiperidine, from step 352aabove, was hydrogenated as described in Example 349g above to give 2.15g of title compound.

Step 352c.8-(4-(methoxymethyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 4-methoxymethylpiperidine, from step352b above, and carrying the product forward as in Example 253 stepsj-k, the title compound was prepared (270 mg). mp 128°-130° C. MS: 405(M+1)⁺ ; ¹ H NMR (CD₃ OD) δ:0.69 (m, 2H), 1.03 (m, 2H), 1.68 (m, 3H),1.98 (m, 1H), 2.12 (m, 1H), 2.27 (m, 1H), 2.79 (s, 3H), 3.28 (m, 1H),3.37 (m, 3H), 3.65 (m, 1H), 3.79 (m, 1H), 4.71 (m, 2H), 8.38 (s, 1H),9.20 (d, 1H, J=12 Hz), 13.88 (s, 1H). Anal. Calcd for C₂₁ H₂₅ N₂ O₅F.0.5 H₂ O: C, 61.02; H, 6.11; N, 6.87; Found: C, 61.01; H, 6.34; N,6.78.

EXAMPLE 3538-(3-amino-3-methylpiperidinyl)-1-cyclpropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 353a. N-benzyl-3-hydroxy-3-methylpiperidine

To a dried system under N₂ was added 400 mL of dry ether and 32.2 mL ofmethyl magnesium bromide, and the solution was cooled to -30° C. To thissolution was added dropwise a solution of 16.626 g ofN-benzyl-3-piperidone (Aldrich) in 50 mL of dry ether. The reactionmixture was then stirred at room temperature for 4 hours. The reactionwas quenched by dropwise addition of satd NH₄ Cl solution with coolinguntil the suspended solid separated. An additional 300 mL of 10% NH₄ Clsolution was then added, and the layers were separated. The aqueouslayer was washed with ether, the organic solution and extracts werecombined, dried over Na₂ SO₄, filtered and evaporated. The residue wasdistilled in a kugelrohr apparatus to give 17.942 g of the titlecompound.

Step 353b. N-benzyl-3-(acetylamino)-3-methylpiperidine

A 21.961 g sample of N-benzyl-3-hydroxy-3-methylpiperidine, prepared asin step 353a above, was dissolved in 16.8 mL of acetonitrile and addeddropwise over 1.5 hours to 134 mL of vigorously stirred 90% sulfuricacid cooled to 0° C. The reaction mixture was stirred for an additional15 min at 0° C., and at room temperature for 6 hours. The reaction wasquenched by pouring the reaction mixture over ice. This solution wasadjusted to pH 12 with 50% NaOH solution and was then extracted withmethylene chloride. The extract was dried over Na₂ SO₄, filtered andevaporated to yield 19.2 of the title compound.

Step 353c. N-benzyl-3-amino-3-methylpiperidine

The sample of N-benzyl-3-(acetylamino)-3-methylpiperidine from theprevious step was stirred with 100 mL of conc. HCl at 110° C. for 36hours. The reaction mixture was poured over 800 g of ice. This mixturewas extracted with methylene chloride. The organic layers were combined,dried over Na₂ SO₄, filtered and evaporated to give the title compound.

Step 353d. N-benzyl-3-(BOC-amino)-3-methylpiperidine

The N-benzyl-3-amino-3-methylpiperidine of the previous step was reactedwith di-t-butyl dicarbonate according to the procedure of Example 350fabove, and the title compound was isolated.

Step 353e. 3-(BOC-amino)-3-methylpiperidine

A 3.32 g sample of N-benzyl-3-(BOC-amino)-3-methylpiperidine washydrogenated according to the procedure of Example 350f above, and 2.50g of the title compound was isolated.

Step 353f.8-(3-amino-3-methylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-(BOC-amino)-3-methylpiperidine,from step 353e above, and carrying the product forward as in Example 253steps j-l, the title compound was prepared (225 mg). MS: 373 (M+1)⁺ ; ¹H NMR (CD₃ OD) δ: 0.69 (m, 2H), 1.05 (m, 2H), 1.53 (m, 3H), 1.80 (m,1H), 2.23 (m, 2H), 2.86 (m, 3H), 3.23 (m, 2H), 3.41 (m, 2H), 3.72 (m,2H), 8.68 (m, 2H). 8.15 (m, 1H), 9.01 (m, 1H), 13.64 (s, 1H). Anal.Calcd for C₂₀ H₂₅ N₃ O₃ ClF.H₂ O: C, 56.14; H, 6.36; N, 9.82; Found: C,55.73; H, 6.43; N, 9.48.

EXAMPLE 3548-(3-pyrrolylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Step 354a. N-CBZ-3-(methanesulformyloxy)piperidine

A 4.0 g sample of N-CBZ-3-hydroxypiperidine (prepared from3-hydroxypiperidine by standard methods) was dissolved in 25 mL ofmethylene chloride and cooled to 0° C. To this was added 3.55 mL oftriethylamine, then a solution of 1.77 mL of methanesulfonylchloride in4 mL of methylene chloride was added dropwise. The reaction mixture wasstirred at 0° C. for 15 min and at room temperature for 1.5 hours. Thereaction was quenched by dilution with methylene chloride and extractionwith 15% NaHCO₃ solution. The layers were separated, and the organiclayer dried over Na₂ SO₄, filtered and evaporated to give 5.02 g of thetitle compound.

Step 354b. N-CBZ-3-pyrrolylpiperidine

A 5.02 g sample of the N-CBZ-3-(methanesulfonyloxy)piperidine from step354a above was dissolved in 8.89 g of pyrrole and heated at 100° C. for20 hours. Excess pyrrole was removed under vacuum, and the residue waswashed with 5% NaHCO₃ solution, water, dried over Na₂ SO₄, filtered andtaken to dryness. The residue was purified by flash chromatography onsilica gel, eluting with 0-1% methanol in methylene chloride to afford0.500 g of the title compound.

Step 354c. 3-pyrrolylpiperidine

A 612 mg sample of N-CBZ-3-pyrrolylpiperidine, from step 354b above, washydrogenated according to the procedure of Example 350f above, and 500mg of the title compound was isolated.

Step 354d.8-(3-pyrrolylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-pyrrolylpiperidine, from step 354cabove, and carrying the product forward as in Example 253 steps j-k, thetitle compound was prepared (157 mg). mp 182°-185° C. MS: 410 (M+1)⁺ ; ¹H NMR (CD₃ OD) δ: 0.71 (m, 2H), 1.03 (m, 2H), 1.93 (m, 2H), 2.26 (m,3H), 2.78 (s, 3H), 2.91-3.78 (m, 6H), 6.19 (m, 2H), 6.77 (m, 2H), 8.23(s, 1H), 9.15 (d, 1H, J=12 Hz), 13.09 (s, 1H). Anal. Calcd for C₂₃ H₂₄N₃ O₃ F.2.25 H₂ O: C, 61.39; H, 5.83; N, 9.34; Found: C, 61.40; H, 5.63;N, 8.94.

EXAMPLE 355 8-(3-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acidhydrochloride

Step 355a. (R)-3-amino-2-piperidone

A sample of D-omithine methyl ester hydrochloride was dissolved in 240mL of methanol, and stirred with 75 g of an anion exchange resin in theOH⁻ form for 4 hours at room temperature. The suspension was filtered,and the filtrate was taken to dryness. The residue was distilled in akugelrohr apparatus to yield 7.59 g of the title compound.

Step 355b. (R)-3-aminopiperidine

A 7.49 g sample of (R)-3-amino-2-piperidone, from step 355a above, wasdissolved in 140 mL of THF, and the solution was cooled to 0° C. To thissolution was carefully added in small portions 3.00 g of lithiumaluminum hydride. The reaction mixture was stirred at room temperaturefor 2 hours. The reaction was quenched with water and NaOH, filtered,and the filter cake was extracted with THF. The solution was dried overNa₂ SO₄, filtered, and evaporated to dryness. The residue was purifiedby distillation.

Step 355c.8-(3-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-acidhydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-aminopiperidine, from step 355babove, and carrying the product forward as in Example 253 steps j-l, thetitle compound was prepared (376 mg). MS: 360 (M+1)⁺ ; ¹ H NMR (CD₃ OD)δ: 0.71 (m, 2H),1.09 (m, 2H), 1.67-2.44 (m, 10H), 3.82 (d, 2H, J=12 Hz),8.20 (s, 1H), 9.25 (d, 1H, J=9 Hz). Anal. Calcd for C₁₉ H₂₃ N₃ O₃ ClF.H₂O: C, 55.14 H, 6.09; N, 10.15; Found: C, 55.50; H, 6.37; N, 9.26.

EXMAPLE 3568-(3-amino-3-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-(BOC-amino)-3-methylpyrrolidine,and carrying the product forward as in Example 253 steps j-l, the titlecompound was prepared (255 mg). MS: 360 (M+1)⁺ ; ¹ H NMR (CD₃ OD) δ:0.69 (m, 2H), 1.07 (m, 2H), 1.63 (s, 3H), 2.31 (m, 3H), 2.74 (s, 3H).3.95 (m, 4H), 8.12 (s, 1H), 9.14 (d, 1H, J=9 Hz). Anal. Calcd for C₁₉H₂₃ N₃ O₃ ClF.H₂ O: C, 55.14; H, 6.09; N, 10.15; Found: C, 55.08; H,6.01; N, 9.77.

EXAMPLE 3578-(3-amino-4-(1',3'-dioxolanyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 357a. N-CBZ-3-amino-4-hydroxy-pyrrolidine

A 27.1 g sample of N-CBZ-3-azido-4-hydroxy-pyrrolidine, prepared as instep 349c above, was hydrogenated for 24 hours under the conditions ofexample 349e above, and 25.4 g of the title compound was obtained.

Step 357b. N-CBZ-3-(CBZ-amino)-4-hydroxy-pyrrolidine

A 25.4 g sample of N-CBZ-3-azido-4-hydroxy-pyrrolidine, from step 357aabove, was dissolved in 129 mL of 1M NaOH, and the solution was cooledto 0° C. A 15.35 mL sample of benzyl chloroformate was dissolved in 20mL of ethanol, and this solution was added dropwise to the vigorouslystirred solution of the pyrrolidine over a 40 min period. The reactionmixture was stirred at 0° C. for 4 hours, then the reaction was quenchedby pouring into 200 mL of water. This mixture was extracted withmethylene chloride, which was dried over Na₂ SO₄, filtered, andevaporated to dryness. The residue was purified by column chromatographyon silica gel, eluting with 0.5-3.5% methanol in methylene chloride toyield 18.77 g of the title compound.

Step 357c. N-CBZ-3-(CBZ-amino)-4-pyrrolidinone

In a dry vessel under N₂ was place 385 mL of methylene chloride, and thesolvent was cooled to 0° C. To this was added 17.32 mL of DMSO, then21.89 mL of phenyl dichlorophosphate was added dropwise over a 30 minperiod. Next was added 34.03 mL of triethylamine over a 30 min period.To this solution was added a solution ofN-CBZ-3-(CBZ-amino)-4-hydroxy-pyrrolidine, from step 357b above, in 100mL of methylene chloride in a dropwise manner over a 45 min period. Thereaction mixture was stirred at 0° C. for 1 hour and at room temperaturefor 20 hours. The reaction was quenched by pouring it into 20% NaClsolution. The mixture was extracted with methylene chloride, which wasdried over Na₂ SO₄, filtered, and evaporated to dryness. The excess DMSOwas removed under vacuum with heating, and the residue was purified bycolumn chromatography on silica gel, eluting with 0 to 1% methanol inmethylene chloride to give 9.2 of the title compound.

Step 357d. N-CBZ-3-(CBZ-amino)-4-(1'-3-dioxolanylyl)pyrrolidine

A0.932 g sample of N-CBZ-3-(CBZ-amino)-4-pyrrolidinone, from step 357cabove, was dissolved in 17 mL of toluene and 0.353 mL of ethylene glycoland 24 mg of p-toluenesulfonic acid were added. The reaction mixture wasstirred at 110° C. for 20 hours, then the reaction was quenched byaddition of 5% NaHCO₃ solution. The mixture was extracted with methylenechloride, which was dried over Na₂ SO₄, filtered, and evaporated todryness. The residue was purified by column chromatography on silicagel, eluting with 2% methanol in methylene chloride to afford 578 mg ofthe title compound.

Step 357e. 3-amino-4-(1'-3-dioxolanylyl)pyrrolidine

A 2.68 g sample of N-CBZ-3-(CBZ-amino)-3-methylpiperidine washydrogenated for 7 days according to the procedure of Example 350fabove, and 937 mg of the title compound was isolated.

Step 357f.8-(3-amino-4-(1',3'-dioxolanyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with3-amino-4-(1',3'-dioxolanyl)pyrrolidine, from step 357d above, andcarrying the product forward as in Example 253 steps j-l, the titlecompound was prepared (324 mg). MS: 404 (M+1)⁺ ; ¹ H NMR (CD₃ OD) δ:0.69(m, 2H), 1.06 (m, 2H), 2.33 (m, 1H), 2.75 (s, 3H), 3.88-4.02 (m, 4H),4.16 (m, 4H), 4.21 (m, 1H), 8.16 (s, 1H), 9.21 (d, 1H, J=9 Hz). Anal.Calcd for C₂₀ H₂₃ N₃ O₅ ClF.H₂ O.HCl: C, 48.59; H, 5.30; N, 8.50; Found:C, 48.80; H, 4.87; N, 8.52.

EXAMPLE 3588-(3-amino-4-hydroxy-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 358a. N-CBZ-3-azido-4-(methoxymethoxy)pyrrolidine

A sample of N-CBZ-3-azido-4-hydroxypyrrolidine, prepared as in Example349c above, was dissolved in 20 mL of methylene chloride, 5.02 mL ofdiisopropylethylamine was added, and 1.64 mL of methoxymethyl chloridewas added dropwise over a 15 min period, with cooling as necessary tomaintain the temperature at ambient. The reaction mixture was stirred atroom temperature for 18 hours, then washed with 0.5M phosphoric acid, 5%NaHCO₃, dried over Na₂ SO₄, filtered, and evaporated to dryness. Theresidue was purified by flash chromatography on silica gel, eluting with0.5% methanol in methylene chloride to yield 1.58 g of the titlecompound.

Step 358b. N-CBZ-3-amino-4-(methoxymethoxy)pyrrolidine

A 2.23 g sample of N-CBZ-3-azido-4-(methoxymethoxy)pyrrolidine, preparedas in step 358a above, was dissolved in 200 mL of ethyl acetate andhydrogenated at room temperature under 4 Atm of H₂ in the presence ofRaNi for 24 hours in a sealed bomb. The catalyst was removed byfiltration, and the solvent was removed under vacuum to give the titleproduct.

Step 358c. N-CBZ-3-(BOC-amino)-4-(methoxymethoxy)pyrrolidine

A 2.04 g sample of N-CBZ-3-amino-4-(methoxymethoxy)pyrrolidine, fromstep 358b above, was dissolved in 20 mL of methylene chloride, and thesolution was cooled to 0° C. To this solution was added 2 mL oftriethylamine, then 2.38 mL of di-t-butyl dicarbonate dissolved in 5 mLof methylene chloride. The reaction mixture was stirred for 30 min at 0°C., at room temperature for 24 hours, and at 40° C. for 8 hours, thenquenched by pouring into 10% NaCl solution. The mixture was extractedwith methylene chloride, which was dried over Na₂ SO₄, filtered, andevaporated to dryness. The residue was purified by column chromatographyon silica gel, eluting with 1% methanol in methylene chloride to give1.35 g of the title compound.

Step 358d. 3-(BOC-amino)-4-(methoxymethoxy)pyrrolidine

A 1.35 g sample of N-CBZ-3-(BOC-amino)-4-(methoxymethoxy)pyrrolidine,from step 358c above, was hydrogenated for 12 days according to theprocedure of Example 350f above, and 874 mg of the title compound wasisolated.

Step 358e.8-(3-amino-4-hydroxy-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-amino-4-hydroxypyrrolidine fromstep 358d above, and carrying the product forward as in Example 253steps j-l, the title compound was prepared (125 mg). MS: 362 (M+1)⁺ ; ¹H NMR (CD₃ OD) δ: 0.69 (m, 2H), 1.08 (m, 2H), 2.31 (m, 1H), 2.73 (s,3H),3.69-4.53 (m, 7H), 8.08 (s, 1H), 9.10 (m, 2H). Anal. Calcd for C₁₈ H₂₁N₃ O₄ ClF.1.5H₂ O: C, 50.89; H, 5.69; N, 9.89; Found: C, 51.38; H, 5.65;N, 9.73.

EXAMPLE 3598-(4-(1-(N-ethylamino)methyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 359a. 4-(N-B OC-N-ethylaminomethyl)pyridine

A 4.00 g sample of 4-(N-ethylaminomethyl)pyridine (Aldrich) wasdissolved in 50 mL of methylene chloride, and the solution was cooled to0° C. To his solution was added 8.19 mL of triethylamine and then 8.01 gof di-t-butyl dicarbonate dissolved in 10 mL of methylene chloride wasadded dropwise. The reaction mixture was stirred for 1 hour at 0° C. andat room temperature for 30 min, then quenched by pouting into 10% NaClsolution. The mixture was extracted with methylene chloride, which wasdried over Na₂ SO₄, filtered, and evaporated to dryness. The residue waspurified by flash chromatography on silica gel, eluting with 1% methanolin methylene chloride to yield 5.52 g of the title compound.

Step 359b. 4-(N-BOC-N-ethylaminomethyl)piperidine

A 5.50 g sample of 4-(N-BOC-N-ethylaminomethyl)pyridine, prepared as instep 359a above, was dissolved in 200 mL of ethyl acetate andhydrogenated at room temperature under 4 Atm of H₂ in the presence ofRaNi for 24 hours in a sealed bomb. The catalyst was removed byfiltration, and the solvent was removed under vacuum to give 1.80 g ofthe title product.

Step 359c.8-(4-(1-(N-ethylamino)methyl)piperidinyl)-1-Cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with4-(N-BOC-N-ethylaminomethyl)piperidine, prepared in step 359b above, andcarrying the product forward as in Example 253 steps j-l, the titlecompound was prepared (488 mg). MS: 402 (M+1)⁺ ; ¹ H NMR (CD₃ OD) δ:0.69 (m, 2H), 1.07 (m, 2H), 1.36 (t, J=7.5 Hz, 3H), 1.91 (m, 4H), 2.36(m, 1H), 2.84 (s, 3H), 2.97 (3.37 (m, 8H), 3.41 (m, 1H), 8.20 (s, 1H),9.26 (d, J=9 Hz, 1H). Anal. Calcd for C₂₂ H₂₉ N₃ O₃ ClF.0.5H₂ O: C,59.12; H, 6.77; N, 9.40; Found: C, 58.74; H, 6.63; N, 9.28.

EXAMPLE 3601-cyclopropyl-7-fluoro-8-(3-hydroxy-4-methylaminopyrrolidinyl)-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 360a. N-CBZ-3-cyano-4-hydroxypyrrolidine

A sample of N-CBZ-3,4-epoxypyrrolidine, prepared as in Example 349babove, was dissolved in 100 mL of ethanol and added to a solution of9.88 g of MgSO₄ and 13.41 g of NaCN in 195 mL of water. The reactionmixture was stirred at 65° C. for 20 hours, cooled, filtered, andextracted with methylene chloride, which was dried over Na₂ SO₄,filtered, and evaporated to dryness to afford 9.0 g of the titlecompound.

Step 360b. N-CBZ-3-aminomethyl-4-hydroxypyrrolidine

A 13.97 g sample of N-CBZ-3-cyano-4-hydroxypyrrolidine, prepared as instep 360a above, was dissolved in 210 mL of methanol containing 40 mL oftriethylamine and hydrogenated at room temperature under 4 Atm of H₂ inthe presence of RaNi for 24 hours in a sealed bomb. The catalyst wasremoved by filtration, and the solvent was removed under vacuum to give14.38 g of the title product.

Step 360c. N-CBZ-3-(BOC-aminomethyl)-4-hydroxypyrrolidine

A 2.73 g sample of N-CBZ-3-aminomethyl-4-hydroxypyrrolidine, from step360b above, was dissolved in 20 mL of methylene chloride, and thesolution was cooled to 0° C. To this solution was added 2.86 g ofdi-t-butyl dicarbonate dissolved in 3 mL of methylene chloride, and thereaction mixture was stirred at 0° C. for 1 hour and at room temperaturefor 18 hours. The reaction was quenched by pouring into 250 mL of water,and the mixture was extracted with methylene chloride, which was driedover Na₂ SO₄, faltered, and evaporated to dryness. The residue waspurified by flash chromatography on silica gel to afford the titlecompound.

Step 360d. 3-hydroxy-4-methylaminopyrrolidine

A sample of N-CBZ-3-(BOC-aminomethyl)-4-hydroxypyrrolidine, from step360c above, was hydrogenated over 10% Pd/C in 100 mL of methanol under 4Atm of H₂ at room temperature for 24 hours. The catalyst was removed byfiltration, the solvent was removed to yield 610 mg of title compound.

Step 360e.1-cyclopropyl-7-fluoro-8-(3-hydroxy-4-methylaminopyrrolidinyl)-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-hydroxy-4-methylaminopyrrolidine,from step 360d above, and carrying the product forward as in Example 253steps j-l, the title compound was prepared (540 mg). MS: 376 (M+1)⁺ ; ¹H NMR (CD₃ OD) δ:0.68 (m, 3H), 0.99 (m, 2H), 2.29 (m, 1H), 2.70 (s, 3H),3.55-4.58 (m, 9H), 8.09 (s, 1H), 9.02 (d, J=9 Hz, 1H). Anal. Calcd forC₁₉ H₂₃ N₃ O₄ ClF.2H₂ O: C, 50.95; H, 6.08; N, 9.38; Found: C, 50.88; H,5.77; N, 9.01.

EXAMPLE 3618-(3-aminomethylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 361a. 3-(N-BOC-aminomethyl)pyridine

Under dry N₂, 15.69 g of di-t-butyldicarbonate was dissolved in 100 mLof CH₂ Cl₂. The flask and contents were cooled in an ice bath, and tothis was added a solution of 6.12 g of 3-(aminomethyl)pyridine in CH₂Cl₂ dropwise with stirring. The solution was stirred at 0°-5° C. for 30min, then stirred at room temperature for 72 hours. The reaction wasdiluted with additional CH₂ Cl₂ (100 mL), then washed with 250 mL ofwater. The water was back-extracted with CH₂ Cl₂, and the organic layerswere combined and dried over Na₂ SO₄. The solution was filtered, and thesolvent was removed on a rotary evaporator to give 13 g of titlecompound.

Step 361 b. 3-(N-BOC-aminomethyl)piperidine

A 10.13 g sample of the compound from step 361 a above was dissolved in250 mL of methanol and reduced over 5 g of 5% Rh/C catalyst at roomtemperature under 4 Atm or H₂ for 18 hours. The catalyst was removed byfiltration, and the solvent was removed under vacuum. The product wasrecrystallized from ethyl acetate, and dried under high vacuum to give3.8 g of product. mp. 64°-65° C.

Step 361c.8-(3-aminomethylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-(N-BOC-aminomethyl)piperidine,prepared in step 361b above, and carrying the product forward as inExample 253 steps j-l, the title compound was prepared (301 mg). mp207°-208° C. MS: 374 (M+1)⁺ ; ¹ H NMR (CD₃ OD) δ: 0.70 (m, 2H), 1.05 (m,2H), 1.45 (m, 2H), 1.90 (m, 2H), 2.10 (m, 2H), 2.35 (m, 1H), 2.84 (s,3H), 3.00 (m, 2H), 3.20 (m, 1H), 3.30 (m, 2H), 8.09 (s, 1H), 8.32 (s,1H), 9.17 (d, 1H, J=12 Hz). Anal. Calcd for C₂₀ H₂₅ N₃ O₃ ClF.1.5H₂ O:C, 50.75; H, 6.18; N, 8.88; Found: C, 50.53; H, 6.20; N, 9.03.

EXAMPLE 3628-(2-aminomethyl-4-morpholinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 362a. N-benzyl-2-chloromethylmorpholine

A flask was charged with 1.5 g (10 mmol) of N-benzyl-ethanolamine, 7.8mL of epichlorohydrin (71 mmol). The reaction mixture was heated at 40°C. for 30 min, then cooled to room temperature. The excessepichlorohydrin was removed under vacuum, and the residue was dissolvedin 30 mL of conc. H₂ SO₄. The solution was heated at 150° C. for 30 minand poured onto 50 g of ice. The solution was adjusted to pH 13 withNaOH, and the mixture was extracted with toluene. The solution was driedover Na₂ SO₄, filtered, the solvent removed, and the residue dried undervacuum to give 193 mg of the title compound. MS m/z: 226, 228 (M+H)⁺.

Step 362b. 2-(N-benzyl-morpholinyl)-N-methylphthalimide

An oven-dried system under positive N₂ pressure was charged with 900 mg(4 mmol) of N-benzyl-3-chloromethylmorpholine dissolved in 20 mL ofDMSO. To this was added 1.48 g (8 mmol) of potassium phthalimide. Thereaction mixture was stirred at 100° C. for 96 hours, then cooled toroom temperature and poured into 50 mL of water. The mixture wasextracted with methylene chloride, the extract washed with water, andthe organic layer was dried over Na₂ SO₄. The solution was filtered, thesolvent was removed under vacuum, and the product was dried under vacuumto give 1.18 g of the title compound. The material was recrystallizedfrom ethanol, separated by filtration, and dried under vacuum to give884 mg of pure title compound.

Step 362c. 4-benzyl-2-aminomethylmorpholine

A system under positive N₂ pressure was charged with 160 mg of3-(N-benzyl-morpholinyl)-N-methylphthalimide, from step 362b above,suspended in 4 mL of ethanol. To this was added 50 μL of hydrazinehydrate, and the reaction mixture was stirred at room temperature for 3hours and at 70° C. for 24 hours. The reaction mixture was cooled toroom temperature and diluted with 10 mL of water. The mixture wasfiltered, and the aqueous layer was adjusted to pH 12 with NaOH andextracted with methylene chloride. The organic extract was dried overNa₂ SO₄, filtered, and the solvent was removed and the product was driedunder vacuum to give 72 mg of the title compound.

Step 362d. 4-benzyl-2-(BOC-aminomethyl)morpholine

An oven-dried system protected from moisture was charged with 198 mg of1-benzyl3-aminomethylmorpholine, prepared as in step 362c above,dissolved in 2 mL of methylene chloride. To this solution was added 250mg of di-t-butyl-dicarbonate. The reaction mixture was stirred at roomtemperature for 24 hours, diluted with 30 mL of methylene chloride, anddried over Na₂ SO₄. The mixture was filtered, and the solvent wasremoved under vacuum. The residue was purified with preparative TLC onsilica gel, developing with 9% methanol in methylene chloride andcollecting the band at Rf=0.48. The product was removed from the silicagel with 300 mL of 10% methanol in methylene chloride, and the solventwas removed under vacuum to give 173 mg of the title compound. MS: 307(M+1)⁺.

Step 362e. 2-(BOC-aminomethyl)morpholine

A 50 mg sample of 4-benzyl-2-(BOC-aminomethyl)morpholine, from step 362dabove, was dissolved in 5 mL of methanol and the benzyl group wasremoved by hydrogenation over under 4 Atm of H₂ over 25 mg of Pd/C atroom temperature for 48 hours. The catalyst was filtered off, and thesolvent was removed to give 33 mg of the title compound.

Step 362f.8-(2-aminomethyl-4-morpholinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-Carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 2-(BOC-aminomethyl)morpholine,prepared as in step 362e above, and carrying the product forward as inExample 253 steps j-l, the title compound was prepared (287 mg). mp209°-210° C. MS: 376 (M+1)⁺, 393 (M+NH₄)⁺ ; ¹ H NMR (CD₃ OD) δ: 0.70 (dd2H, J=4.5, 1.5 Hz), 1.09 (dd, 2H, J=l.5, 4.5 Hz), 2.38 (m, 1H), 2.88 (s,3H), 3.05 (m, 2H), 3.20 (m, 2H), 3.40 (m, 2H), 3.50 (m, 2H), 3.90 (m,2H), 4.10 (dd, 1H, J=1.5, 12 Hz), 8.03 (s, 1H), 8.15 (s, 1H), 9.23 (d,1H, J=9 Hz), Anal. Calcd for C₁₉ H₂₃ N₃ O₄ ClF.2.25H₂ O: C, 50.45; H,6.13; N, 9.29; Found: C, 50.63; H, 6.17; N, 9.11.

EXAMPLE 3638-(3-(1-(methylamino)methypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 363a. 3-(N-BOC-N-methylamino)methyl)pyridine

To a dry flask under N₂ was added 84.7 mg (2.2 mmol) of NaH (minoilwashed with dry hexane) and 2 mL of dry THF. The mixture was cooled inan ice bath and 416 mg of 3-(N-BOC-aminomethyl)piperidine, from Example361b above, in 4 mL of dry THF was added dropwise. The mixture wasstirred at 0°-5° C. for 1 hour after addition was complete, and 0.125 mLof methyl iodide was added. The mixture was stirred at 0°-5° C. for 30min, then warmed to room temperature and stirred for 24 hours. Thereaction was quenched by pouring it into 30 mL of said NaCl solution,and the mixture was extracted with 3×30 mL of methylene chloride. Theorganic extracts were combined, dried over Na₂ SO₄, filtered andconcentrated on a rotary evaporator to give 430 mg of title compound.

Step 363b. 3-(N-BOC-N-methylamino)methyl)piperidine

A 1.16 g sample of the compound from step 361a above was dissolved in 50mL of methanol and reduced over 1.16 g of 5% Rh/C catalyst at roomtemperature under 4 Atm or H₂ for 18 hours. The catalyst was removed byfiltration, and the solvent was removed under vacuum. The product wasrecrystallized from ethyl acetate, and dried under high vacuum to give1.18 g of product. MS m/z: 229 (M+H)⁺.

Step 363c.8-(3-(1-(methylamino)methypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with3-(N-BOC-N-methylamino)methyl)piperidine prepared according to step 363aabove, and carrying the product forward as in Example 253 steps j-l, thetitle compound was prepared (535 mg). mp 246°-247° C. MS: 388 (M+1)⁺ ; ¹H NMR (CD₃ OD) δ: 0.70 (dd, 2H, J=4.5 Hz), 1.07 (dd, 2H, J=7.8 Hz), 1.50(m, 2H), 1.90 (m, 4H), 2.10 (m, 2H), 2.21 (m, 2.21 (m, 1H), 2.72 (s,3H), 2.85 (s, 3H), 3.00 (m, 2H), 8.10 (s, 1H), 8.32 (s, 1H), 9.18 (d,1H, J=9 Hz), Anal. Calcd for C₂₁ H₂₇ N₃ O₃ ClF.H₂ O: C, 57.08; H, 6.61;N, 9.51; Found: C, 56.93; H, 6.68; N, 10.23.

EXAMPLE 3648-(3-(methyl(methylenedioxy)methyl)piperidinyl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with3-(methyl(methylenedioxy)methyl)piperidine prepared according toEuropean Patent Application 342, 675, and carrying the product forwardas in Example 253 steps j-k, the title compound was prepared (443 mg).mp 117°-118° C. MS: 419 (M+1)⁺ ; ¹ H NMR (CDCl₃) δ:0.70 (m, 2H), 1.03(m, 2H), 1.40 (m, 2H), 1.71 (m, 6H), 2.80 (s, 3H), 3.10 (dt, 1H, J=3, 12Hz), 8.04 (dd, 2H, J=7.5 Hz), 8.32 (s, 1H), 9.18 (d, 1H, J=12 Hz); Anal.Calcd for C₂₂ H₂₇ N₂ O₅ F: C, 63.15; H, 6.50; N, 6.69; Found: C, 63.02;H, 6.42; N, 6.64.

EXAMPLE 3658-(3-(S)-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-(S)-(N-BOC-amino)piperidine andcarrying the product forward as in Example 253 steps j-l, the titlecompound was prepared (500 mg). mp 220°-221° C. MS: 360 (M+1) ⁺, 377(M+NH₄)⁺ ; ¹ H NMR (CD₃ OD) δ:0.70 (m, 2H, J=6 Hz), 1.10 (m, 2H, J=6Hz), 1.72 (m, 2H), 2.05 (m, 3H), 2.28 (m, 2H), 2.40 (m, 2H), 2.86 (s,3H), 3.90 (m, 1H), 8.18 (s, 1H), 9.22 (d, 1H, J=9 Hz); Anal. Calcd forC₁₉ H₂₃ N₂ O₅ ClF.1.5 H₂ O: C,53.97; H, 6.20; N, 9.94; Found: C, 54.28;H, 6.61; N, 8.85.

EXAMPLE 3668-(3-(S)-(N-ethyl-N-methylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Step 366a. (S)-3-acetylamino-1-benzylpyrrolidine

To 1.30 g (7.38 mmol) of 3-amino-1-benzylpyrrolidine and 1.7 mL (12mmol) of triethylamine in 25 mL of ethyl acetate stirred at roomtemperature was added 1.1 mL (12 mmol) of acetic anhydride, and thereaction was stirred for 1 hour. The solvent was removed, and theresidue was treated with 1:1 20% K₂ CO₃ :brine, then extracted withmethylene chloride. The organic extract was dried over Na₂ SO₄,filtered, the solvent was removed under vacuum, and the residue wasdried under high vacuum for 16 hours to give 1.71 g of the titlecompound. MS: 219 (M+1)⁺ ; Anal. Calcd for C₁₃ H₁₈ N₂ O: C,68.69; H,8.42; N, 12.32; Found: C, 68.75; H, 8.00; N, 12.27.

Step 366b. (S)-3-ethylamino-1-benzylpyrrolidine

To 1.70 g (7.4 mmol) of the compound from step 366a above in 20 mL ofTHF was added 850 mg of lithium aluminum hydride, and the mixture wasstirred at room temperature for 72 hours. The reaction was quenched withwater and NaOH, stirred for 1 hour, filtered, and the filter cake wasextracted with methylene chloride. The aqueous layers were extractedwith methylene chloride, and the organic extracts were combined. Thesolution was dried over Na₂ SO₄, filtered, and the solvent was removedunder vacuum to give 1.71 g of the title compound. ¹ H NMR (CDCl₃) δ:1.09 (t, 3H), 1.30-1.51 (m, 1H), 1.48-1.53 (m, 1H), 2.06-2.21 (m, 1H),2.34 (dd, 1H), 2.58 (q, 2H), 2.47-2.68 (m, 2H), 2.77 (dd, 1H), 3.26-3.37(m, 1H), 3.50 (s, 2H), 7.19-7.40 (m, 5H).

Step 366c. (S)-3-(N-BOC-N-ethylamino)-1-benzylpyrrolidine

To a 1.7 g sample of the compound from step 366b above dissolved in 3 mLof methylene chloride was added 1.94 g (8.9 mmol) of butoxycarbonylanhydride, and the reaction was stirred for 16 hours. The solvent wasremoved under vacuum, and the residue was chromatographed on silica gel,eluting with 1; 1 hexane:ethyl acetate to give 1.8 g of the titlecompound. MS: 305 (M+1)⁺ ; ¹ H NMR (CDCl₃) δ: 1.11 (t, 3H), 1.44 (s,9H), 3.25 (q, 2H), 724-7.47 (m, 5H). Anal. Calcd for C₁₈ H₂₈ N₂ O₂:C,68.00; H, 9.35; N, 8.81; Found C, 68.05; H, 8.73; N, 8.85.

Step 366d. (S)-3-(N-ethyl-N-methylamino)-1-benzylpyrrolidine

To a 1.8 g (5.9 mmol) sample of the compound from step 366c above in 20mL of THF was added 800 mg of LAH, and the reaction was stirred for 48at reflux conditions. The reaction was cooled to room temperature, and0.8 mL of water was added dropwise with stirring, followed by 0.8 mL of15% NaOH similarly, and finally 2.4 mL of water, and the mixture wasstirred for 2 hours at room temperature. The mixture was filtered, thefilter cake washed with methylene chloride, the filtrate concentratedunder vacuum to give the crude title product. This material wasdissolved in acetic acid and filtered, methanol was added and thesolvent removed, and the residue repeatedly dissolved in methanol andstripped. The residue was taken up in water, adjusted to pH 10-11 withK₂ CO₃, saturated with NaCl, then this solution was extracted with 10%methanol in CHCl₃. The extract was dried over Na₂ SO₄, filtered and thesolvent was removed to give 603 mg of the title product. MS: 219 (M+1)⁺; ¹ H NMR (CDCl₃) δ: 1.06 (t, 3H), 1.93-2.09 (m, 1H), 2.20 (s, 3H),2.28-2.60 (br, 4H), 2.66-2.77 (m, 1H), 2.82 (dd, 1H), 2.96-3.14 (m, 1H),3.60 (q, 2H), 7.18-7.41 (m, 5H).

Step 366e. (S)-3-(N-ethyl-N-methylamino)pyrrolidine

A 1.3 g sample of the compound from step 366d above was dissolved in 50mL of acetic acid and 0.5 mL of HCl, 0.13 g of 10% Pd/C was added andthe sample hydrogenated under 4 Atm of H₂. Additional amounts ofcatalyst and HCl were added before the reaction was complete. Thesolution was filtered, then the solvent was removed with repeatedaddition and removal of methanol. The residue was dissolved in water,which was adjusted to pH 10-11 with K₂ CO₃, saturated with NaCl, andextracted repeatedly with 10% methanol in CHCl₃. The extract was driedover Na₂ SO₄, filtered, and taken to dryness to give 603 mg of the titlecompound. HRMS (M+1)⁺ : calc: 129.1936; found, 129.1392.

Step 366f.8-(3-(S)-(N-ethyl-N-methylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with(S)-3-(N-ethyl-N-methylamino)-pyrrolidine from step 366e above andcarrying the product forward as in Example 253 steps j-k, the titlecompound was prepared. MS: 416 (M+1)⁺ ; ¹ H NMR (CDCl₃) δ: 0.5-0.6M,1H), 0.6-0.7 (m, 1H), 0.8-0.95 (m, 2H), 1.1 (t, 3H), 1.4 (t, 3H),1.9-2.0 (m, 1H), 2.1-2.2 (m, 1H), 2.25 (s, 3H), 2.33 (s, 3H), 3.6-3.7(m, 4H), 3.7-3.9 (m, 1H), 3.9-4.0 (m, 1H), 4.12 (dd, 1H), 4.4 (q, 2H),8.13 (s, 1H), 9.25 (d, 2H).

EXAMPLE 3671-cyclopropyl-8-(4-(2'-(N-methylamino)methyl-1',3'-dioxolanyl)piperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Step 367a. N-CBZ-4-(4'-bromomethyl-1',3'-dioxolanyl)piperidine,

A 17.48 g sample of N-CBZ-4-oxopiperidine, prepared as in Example 350babove, was dissolved in 325 mL of toluene, and 16.40 mL of3-bromo-1,2-propanediol and 713 mg of p-toluenesulfonic acid were added.The reaction mixture was heated at reflux (120°-125° C.) for 24 hourswhile collecting the water of reaction in a Dean-Stark trap. Thereaction mixture was cooled to room temperature, then washed with 5%NaHCO₃ and water, dried over Na₂ SO₄, filtered, and taken to dryness.The residue was purified by flash chromatography on silica gel, elutingwith 0-to-1.5% methanol in methylene chloride to yield 26.5 g of thetitle compound.

Step 367b. N-CBZ-4-(4'-(methylaminomethyl)-1',3'-dioxolanyl)piperidine

A 7.29 g sample of N-CBZ-4-(4'-bromomethyl-1',3'-dioxolanyl)piperidine,from step 367a above, was heated with excess methylamine, and 3.427 g ofthe title compound was isolated and purified.

Step 367c.N-CBZ-4-(4'-(N-BOC-N-methylaminomethyl)-1',3'-dioxolanyl)piperidine

A 3.43 g sample ofN-CBZ-4-(4'-(methylaminomethyl)-1',3'-dioxolanyl)piperidine, from step367b above, was dissolved in 30 mL of methylene chloride, to which wasadded 2.98 mL of triethylamine followed by dropwise addition of 3.50 gof di-t-butyl dicarbonate in 20 mL of methylene chloride. The reactionmixture was stirred at 35° C. for 5 hours and at room temperature for 15hours. The mixture was diluted with methylene chloride and washed withwater. The extract was dried over Na₂ SO₄, filtered, and taken todryness to obtain 4.29 g of title compound.

Step 367d. 4-(4'-(N-BOC-N-methylaminomethyl)-1',3'-dioxolanyl)piperidine

A sample ofN-CBZ-4-(4'-(N-BOC-N-methylaminomethyl)-1',3'-dioxolanyl)piperidine,from step 367c above, was hydrogenated over 10% Pd/C in 200 mL ofmethanol under 4 Atm of H₂ at room temperature for 24 hours. Thecatalyst was removed by filtration, and the solvent was removed to yieldthe title compound.

Step 367e.1-cyclopropyl-8-(4-(2'-(N-methylamino)methyl-1',3'-dioxolanyl)piperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with4-(4'-(N-BOC-N-methylaminomethyl)-1',3'-dioxolanyl)piperidine, preparedin step 367d above, and carrying the product forward as in Example 253steps j-k, 199 mg of the title compound was prepared. IR (KBr) cm⁻¹ :3300 (br), 2850 (br), 1700(s), 1610 (m), 1530 (s), 790 (m). MS (CDI/NH3)m/z (M+H)⁺ : 446 base. NMR (d₆ -DMSO): 9.18 (d, 1H), 8.00 (s, 1H),3.69-4.57 (m, 4H), 2.95-3.25 (m, 5H), 2.76 (s, 3H), 2.48 (m, 3H), 2.40(m, 1H), 1.88 (m, 4H), 1.02 (m, 2H), 0.65 (m, 2H). Anal. Calcd for C₂₃H₂₉ ClFN₃ O₅ :.2 H₂ O: C,53.33; H, 6.42; N, 8.11; Found: C, 53.62; H,6.38; N, 8.32.

EXAMPLE 3681-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3,3,0]octan-1-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Step 368a. N-benzyl-3-aza-6-oxobicyclo[3,3,0]octane

A 32.69 g sample of N-methoxymethyl-N-(trimethylsilylmethyl)-benzylaminewas dissolved in 30 mL of methylene chloride, and the solution wascooled to 0° C. To this solution was added 9.5 mL of2-cyclopentene-1-one and 1.75 mL of trifluoroacetic acid, and thereaction mixture was stirred at 0° C. for 0.5 hours and at roomtemperature for 24 hours. The reaction was quenched with water, and themixture was extracted with methylene chloride, which was dried over Na₂SO₄, filtered, and taken to dryness to obtain 28.27 g of the titlecompound.

Step 368b. N-benzyl-3-aza-6-hydroxy-6-methylbicyclo[3,3,0]octane

In dry ether and under N₂, the compound from step 368a was reacted withmethyl magnesium bromide at -30° C. Mter standard workup, the titlecompound was isolated.

Step 368c. N-benzyl-3-aza-6-(acetylamino)-6-methylbicyclo[3,3,0]octane

The compound of step 368b was reacted with acetonitrile in the presenceof concentrated sulfuric acid. The reaction was quenched with water, andthe product was extracted into methylene chloride, which was dried overNa₂ SO₄, filtered, and taken to dryness to obtain the title compound.

Step 368d. N-benzyl-3-aza-6-amino-6-methylbicyclo[3,3,0]octane

The acetyl group was removed from the compound of step 368c by reactionwith conc. HCl. The reaction mixture was made basic with NaOH, and theproduct was extracted into methylene chloride, which was dried over Na₂SO₄, filtered, and taken to dryness to obtain the title compound.

Step 368e. N-benzyl-3-aza-6-(BOC-amino)-6-methylbicyclo[3,3,0]octane

The compound from step 368d was reacted with di-t-butyl dicarbonate inthe presence of triethylamine. The reaction was quenched with water, andthe product was extracted into methylene chloride, which was dried overNa₂ SO₄, filtered, and taken to dryness to obtain the title compound.

Step 368f. 3-aza-6-(BOC-amino)-6-methylbicyclo[3,3,0]octane

The benzyl group was removed from the compound of step 368f byhydrogenation in the presence of Pd/C. The catalyst was removed byfiltration, and the product was obtained by evaporation of the solvent.

Step 368g.1-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3,3,0]octan-1-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with3-aza-6-(BOC-amino)-6-methylbicyclo[3,3,0]-octane, from step 369g above,and carrying the product forward as in Example 253 steps j-k, 418 mg ofthe tiff(compound was prepared. IR (KBr) cm⁻¹ : 3340 (br), 2860 (br),1700 (m), 1610 (m), 1430,(s), 1370 (m). MS (CDI/NH3) m/z (M+H)⁺ : 400base. NMR (CD₃ OD): 9.12 (m, 1H), 8.03 (s, 1H), 3.94 (m, 2H), 3.78 (m,1H), 3.57 (m, 2H), 2.83 (m, 1H), 2.78 (m, 3H), 2.31 (m, 1H), 1.88 (m,2H), 2.19 (m, 2H), 1.50 (s, 3H), 1.07 (m, 2H), 0.68 (m, 2H). Anal. Calcdfor C₂₂ H₂₇ ClFN₃ O₃ O.1.5 H₂ O C,57.62; H, 6.37; N, 9.06; Found: C,58.02; H, 6.64; N, 9.23.

EXAMPLE 3691-cyclopropyl-8(3-fluoromethylpiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine

Step 369a. N-BOC-3-hydroxymethylpiperidine

A sample of 3-hydroxymethylpiperidine (2.0 g,17.4 mmol) was suspended in60 mL of water and cooled to 0C. Sodium bicarbonate (2.63 g, 31 mmol)was added in one portion, then benzyl chloroformate (2.60 ml, 18.3 mmol)was added dropwise in 10 ml of diethyl ether. After stirring for 4 hoursat 0C., the reaction was poured into 150 ml water and extracted withmethylene chloride (3×100 ml). The combined organic layers were driedover sodium sulfate, then filtered and the filtrate evaporated todryness to yield 3.74 g (86%).

Step 369b. N-BOC-3-fluoromethylpiperidine

This compound from step 369a (3.74 g, 15 mmol) was then dissolved in 10ml of methylene chloride and added dropwise to a solution ofdiethylaminosulfur trifluoride (2.59 ml, 19.5 mmol) in 10 ml ofmethylene chloride at -78C. After the addition, the reaction was stirredat room temperature for 16 hours. 10 ml of water, then 30 ml of 1Msodium hydroxide was added dropwise to the reaction, then the productwas extracted into methylene chloride (3×75 ml). The combined organiclayers were dried over sodium sulfate, filtered, and the filtrate wasevaporated to dryness. The product was purified by flash chromatography(100% methylene chloride) to yield 2.42 g (64%).

Step 369c. 3-fluoromethylpiperidine

The amine was deprotected under hydrogenation conditions in methanolusing palladium on carbon (2 g). After 16 h at room temperature and 4atm, the catalyst was filtered off and the filtrate concentrated toyield: 808 mg (68%) of the desired amine.

Step 369d.1-cyclopropyl-8-(3-fluoromethylpiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 3-fluoromethylpiperidine, from step369d above, and carrying the product forward as in Example 253 stepsj-k, 198 mg of the title compound was prepared. IR (KBr) cm⁻¹ : 2950(br), 1650 (s), 1470 (s), 1440 (s), 1350 (m). MS (CDI/NH3) m/z (M+H)⁺ :377 base. NMR (CDCl₃): 9.22 (d, 1H, J=9 Hz), 8.37 (s, 1H), 4.21-4.53 (m,4H), 3.14-3.67 (m, 7H), 2.79 (s, 3H), 2.25 (m, 1H), 1.04 (m, 2H), 0.72(m, 2H). Anal. Calcd for C₂₀ H₂₂ F₂ N₂ O₃ : C, 63.82; H, 5.89; N, 7.44;Found: C, 63.35; H, 5.83; N, 6.85.

EXAMPLE 3701-cyclopropyl-8-(4-(N,N-dimethyl)aminopiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Step 370a. 4-(N,N-dimethyl)aminopiperidine

4-(N,N-dimethyl)aminopyridine (1.0 g, 8.2 mmol) was subjected tohydrogenation conditions in 100 ml methanol using Rhodium (50 mg) atroom temperature and 4 atm for 72 hours. The catalyst was filtered offand the filtrate was evaporated to yield 100% of the desired amine.

Step 370b.1-cyclopropyl-8-(4-(N,N-dimethyl)aminopiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with 4-(N,N-dimethyl)aminopiperidine,from step 370a above, and carrying the product forward as in Example 253steps j-k, 345 mg of the title compound was prepared. IR (KBr) cm⁻¹ :2950 (br), 1710 (m), 1610 (m), 1470 (s), 1440 (s). MS (CDI/NH3) m/z(M+H)⁺ : 388 base. Anal. Calcd for C₂₁ H₂₇ ClFN₃ O₃ : C, 59.50; H, 6.42;N, 9.91; Found: C, 59.72; H, 6.69; N, 9.33.

EXAMPLE 3711-cyclopropyl-8-(6-amino-3-azabicyclo[3,3,0]octyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Step 371a. 3-aza-3-benzyl-6-(hydroxylimino)bicyclo[3,3,0]octane

A 3.24 sample of 3-aza-6-oxobicyclo[3,3,0]octane, prepared as in Example368a above, was dissolved in 40 mL of THF. Hydroxylamine hydrochloride(3.14 g) was dissolved in 60 mL of water and 4.05 g of NaHCO₃ was addedto neutralize the salt. The neutral hydroxylamine solution was added tothe THF solution, and the reaction mixture was stirred vigorously atroom temperature for 18 hours. The THF was removed from the mixtureunder vacuum, and the aqueous solution was extracted with methylenechloride, which was dried over sodium sulfate, filtered and evaporatedto dryness to yield 2.80 g of the title compound.

Step 371b. 3-aza-3-benzyl-6-aminobicyclo[3,3,0]octane

A 29.37 g sample of 3-aza-6-(hydroxylimino)bicyclo[3,3,0]octane,prepared as in step 371a above, was dissolved in 1 L of methanol andhydrogenated at 4 Atm of H₂ over 58.74 g of RaNi catalyst for 24 hours.The catalyst was filtered off, and the solvent was evaporated to affordthe title compound.

Step 371c. 3-aza-3-benzyl-6-(BOC-amino)bicyclo[3,3,0]octane

A 2.63 g sample of 3-aza-3-benzyl-6-aminobicyclo[3,3,0]octane, from step371b above, was dissolved in 25 mL of methylene chloride, 3.39 mL oftriethylamine was added, and the solution was cooled to 0° C. A 3.98 gsample of di-t-butyl dicarbonate was dissolved in 6 mL of methylenechloride and added dropwise to the first solution. The reaction mixturewas stirred 30 min at 0° C. and at room-temperature for 18 hours, thequenched by rapid addition to water. The mixture was extracted withmethylene chloride, which was dried over sodium sulfate, filtered andevaporated to dryness. The residue was purified by columnchromatography, eluting with 2% methanol in methylene chloride to affordthe title compound.

Step 371d. 3-aza-6-(BOC-amino)bicyclo[3,3,0]octane

The compound from step 371c above was dissolved in 150 mL of methanoland hydrogenated for 23 hours at room temperature and 4 Atm of H₂ over1.5 g of 10% Pd/C catalyst The catalyst was filtered off, and thesolvent was evaporated to afford the title compound.

Step 371e.1-cyclopropyl-8-(6-amino-3-azabicyclo[3,3,0]octyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with6-(BOC-amino)-3-azabicyclo[3,3,0]octane, from step 371d above, andcarrying the product forward as in Example 253 steps j-k, 298 mg of thefinal compound was prepared. IR (KBr) cm⁻¹ : 2900 (br), 1700 (m), 1610(m), 1430 (s), 1380 (m). MS (CDI/NH3) m/z (M+H)⁺ : 386 base. NMR (CD₃OD): 9.04 (d, 1H, J=9 Hz), 7.97 (s, 1H), 3.92 (m, 2H), 3.78 (m, 2H),3.57 (m, 1H), 3.15 (m, 1H), 3.04 (m, 1H), 2.76 (s, 3H), 2.29 (m, 1H),1.69-2.21 (m, 3H), 1.08 (m, 2H), 0.67 (m, 2H). Anal. Calcd for C₂₁ H₂₅ClFN₃ O₃.1.5 H₂ O. HCl: C, 51.97; H, 6.02; N, 8.66; Found: C, 52.07; H,5.81; N, 8.48.

EXAMPLE 3721-cyclopropyl-8-((2-aza-4-(dimethylaminomethyl)bicyclo[4,3,0]non-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizinecarboxylic acid hydrochloride

Step 372a. 2-aza-4-dimethylaminomethylbicyclo[3,3,0]nonane

A 1 g sample of 3-dimethylaminomethylindole was hydrogenated over Pd/Cin acetic acid/HCl, the catalyst removed by filtration, and the solventdiluted with water, adjusted to pH 11, and extracted with ethyl acetate.The solvent was dried and evaporated to afford the title compound.

Step 372b.1-cyclopropyl-8-((2-aza-4-(dimethylaminomethyl)bicyclo[4,3,0]non-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizinecarboxylic acid hydrochloride

Following the procedure of Example 253 step j, replacing the3-BOC-aminopyrrolidine thereof with2-aza-4-(dimethylaminomethyl)bicyclo[4,3,0]-nonane, from step 372aabove, and carrying the product forward as in Example 253 steps j-k, 354mg of the final compound was prepared. IR (KBr) cm⁻¹ : 3400 (br), 2950(m), 2600 (br), 1720 (m), 1610 (m), 1430 (s), 1380 (m). MS (CDI/NH3) m/z(M+H)⁺ : 442 base. NMR (CDCl₃): 9.07 (d, 1H, J=9 Hz), 8.28 (s, 1H), 4.47(m, 1H), 4.04 (m, 1H), 3.60 (m, 1H), 3.18 (m, 2H), 2.75 (s, 3H), 2.49(m, 1H), 2.27 (m, 1H), 1.26 (m, 2H), 1.00-1.90 (m, 9H), 2.91 (s, 6H),0.70 (m, 2H). Anal. Calcd for C₂₅ H₃₃ ClFN₃ O₃.1.25 H₂ O: C, 60.59; H,7.73; N, 8.48; Found: C, 60.07; H, 7.71; N, 8.15.

EXAMPLE 3231-cyclopropyl-8-(3-aza-6-(L-alanylamino)-6-methylbicyclo[3,3,0]octane)-7-fluoro-9-methyl-4-oxo-4H-quinolizinecarboxylic acid hydrochloride

A 50 mg sample of1-cyclopropyl-8-(3-aza-6-(L-alanylamino)-6-methylbicyclo[3,3,0]octane)-7-fluoro-9-methyl-4-oxo-4H-quinolizinecarboxylic acid hydrochloride, from Example 368, was dissolved in 3 mLof DMF, and the solution was cooled to 0° C. A 0.044 mL sample ofdiisopropylethylamine was added, followed by 35 mg ofN-BOC-L-alanyl-N-hydroxysuccmimide, and the reaction was stirred at 0°C. for 20 min and at room temperature for 48 hours. The solution waspoured into a large volume of water, and the product was filtered offand dried. IR (KBr) cm⁻¹ : 2950 (br), 1680 (m), 1430 (s). MS (CDI/NH3)m/z (M+H)⁺ : 471 base. Anal. Calcd for C₂₅ H₃₂ ClFN₄ O₄.H₂ O: C, 57.19;H, 6.14; N, 10.67; Found: C, 57.16; H, 6.48; N, 9.90.

EXAMPLE 374 (3R,1R)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was dissolved in 8 mL ofanhydrous acetonitrile, reacted with (3R,1R)-3-(1-(N-methyl)amino)propyl)pyrrolidine (prepared as described byHayakawa et al., U.S. Pat. No. 5,098,912, issued Mar. 24, 1992, usingmodifications for chiral products described by Plummer et al., Tetr.Lett. 34:7529-32 (1993)), and carded forward as described in Example 253j-1, omitting the deprotecting step, to give the title product. MS 402(M+H)⁺ ; ¹ H NMR (D₆ -DMSO) δ: 0.6-0.7 (m, 3H), 0.9 (t, 3H), 1-1.5 (m,2H), 16-1.95 (m, 4H), 2.1-2.2 (m, 1H), 2.6-2.65 (m, 1H), 2.60 (s, 2H),2.7 (s, 3H), 3.45-3.55 (m, 1H), 3.7-3.75 (m, 2H), 3.95-4 (m, 1H), 8.25(s, 1H), 9.1 (d, 2H)

EXAMPLES 375-408

Following the procedures of Steps 253j, 253k and 253l above, replacingthe 3-BOC-aminopyrrolidine of Step 253j with the appropriate unprotectedor BOC-protected reagent, the compounds of Examples 375-412 are preparedas shown in Table 13, below.

                  TABLE 13                                                        ______________________________________                                         ##STR224##                                                                   Example # R.sup.2                                                             ______________________________________                                        375                                                                                      ##STR225##                                                         376                                                                                      ##STR226##                                                         377                                                                                      ##STR227##                                                         378                                                                                      ##STR228##                                                         379                                                                                      ##STR229##                                                         381                                                                                      ##STR230##                                                         382                                                                                      ##STR231##                                                         383                                                                                      ##STR232##                                                         384                                                                                      ##STR233##                                                         385                                                                                      ##STR234##                                                         386                                                                                      ##STR235##                                                         387                                                                                      ##STR236##                                                         388                                                                                      ##STR237##                                                         389                                                                                      ##STR238##                                                         390                                                                                      ##STR239##                                                         391                                                                                      ##STR240##                                                         392                                                                                      ##STR241##                                                         393                                                                                      ##STR242##                                                         394                                                                                      ##STR243##                                                         395                                                                                      ##STR244##                                                         396                                                                                      ##STR245##                                                         397                                                                                      ##STR246##                                                         398                                                                                      ##STR247##                                                         399                                                                                      ##STR248##                                                         400                                                                                      ##STR249##                                                         401                                                                                      ##STR250##                                                         402                                                                                      ##STR251##                                                         403                                                                                      ##STR252##                                                         404                                                                                      ##STR253##                                                         405                                                                                      ##STR254##                                                         406                                                                                      ##STR255##                                                         407                                                                                      ##STR256##                                                         408                                                                                      ##STR257##                                                         409                                                                                      ##STR258##                                                         410                                                                                      ##STR259##                                                         411                                                                                      ##STR260##                                                         412                                                                                      ##STR261##                                                         ______________________________________                                    

EXAMPLE 413 (3R,1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4H-quinolizine-3-carboxylicacid hydrochloride

Step 4 13a. (S)-N-BOC-O-(t-butyldimethylsilyl)serine methyl ester

A 7 g (31.96 mmol) sample of ((S)-N-BOC-serine methyl ester (obtainedfrom Aldrich) was dissolved in pyridine and cooled in an ice bath. Tothis stirred solution was added dropwise 5.54 g (36.76 mmol) oft-butyldimethylsilyl chloride (TBDMSC) dissolved in 40 mL of pyridine.After all reagents were added the reaction was stirred for 4 hours atroom temperature. An additional 0.5 g of TBDMSC was added and thereaction was stirred for an additional 2 hours. To the mixture was thenadded 2.5 equivalents of imidazole in 14 mL of DMF, and the reaction wasstirred for 2 hours. The solvents were removed under reduced pressure,and the residue was dissolved in ethyl acetate, which was washed withwater and brine. The solvent was removed to give the title compound as ayellow oil. MS 334 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ:0.11 (s, 6H), 0.86 (s,9H), 1.46 (s, 9H), 3.74 (s, 3H), 3.82 (dd, 1H). 4.04 (dd, 1H), 4.36 (m,1H), 5.35 (br, 1H).

Step 413b. (S)-2-(BOC-amino)-3-(t-butyldimethylsilyloxy)-1-propanol

A solution of the compound from step 413a above (9.6 g, 28.83 mmol) in44 mL of THF was added dropwise to a cooled (ice bath) suspension of 570mg (14.84 mmol) of LAH in 15 mL of THF under N₂ atmosphere. The mixturewas stirred for 1.5 hours, the reaction was quenched with water and 50%NaOH, filtered, and the filtrate evaporated to obtain the crude product.An oil was obtained, which was purified by chromatography on silica gel,eluting with 15-20% ethyl acetate:hexane to give 3.465 g of the titleproduct as a colorless oil. MS 306 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 0.08(s,6H), 0.90 (s, 9H), 1.45 (s, 9H), 2.68 (br, 1H), 3.68 (m, 2H), 3.81 (d,2H), 3.85 (m, 1H), 5.15 (br, 1H).

Step 413c. (S)-2-(BOC-amino)-3-(t-butyldimethylsilyloxy)-1-propanol

To a solution of the compound from step 413b above (3.47 g, 11.36 mmol)in 6 mL of DMSO cooled to 0° C. was added dropwise 5.2 mL (37.49 mmol)of triethylamine. Pyridine.SO₃ complex (5.424 g, 34.08 mmol) wasdissolved in 21 mL of DMSO and added to the first solution, and thereaction was stirred for 1.5 hours after the addition was complete. Thesolution was poured into 120 mL of cold brine, and the mixture waswashed 3× with ethyl acetate. The extract was washed with water, driedover MgSO₄, filtered and the solvent was removed under vacuum to give3.9 g of a yellow oil, which was taken directly to the next step.

Step 413d. (S)-4-(BOC-amino)-5-(t-butyldimethylsilyoxy)-2-pentenoic acidethyl ester

To a solution of the compound from step 413c above (11.36 mmol) in 24 mLof CH₂ Cl₂ and cooled in an ice bath was added dropwise 3.958 g (11.36mmol) of (carboethoxymethylene)triphenylphosphorane in 13 mL of CH₂ Cl₂.After addition was complete, the reaction was stirred for 16 hours atroom temperature. The solvent was removed, and the residue was purifiedby column chromatography on silica gel, eluting with 3-10% ethylacetate:hexane, to give 3.93 g of a colorless oil. MS 374 (M+H)⁺ ; ¹ HNMR (CDCl₃) δ: 0.05 (d, 6H), 0.88 (s, 9H), 1.27 (t, 3H), 1.46 (s, 9H),3.72 (m, 2H), 4.19 (q, 2H), 4.36 (br, 1H), 5.98 (dd, 1H), 6.91 (dd, 1H).

Step 413e.(S)-4-(BOC-amino)-5-(t-butyldimethylsilyloxy)-3-(nitromethyl)-pentanoicacid ethyl ester

To a solution of the compound from step 413d above (3.9 g, 10.46 mmol)in 6 mL of nitromethane cooled in an ice bath was added 1.56 mL (10.46mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene dropwise under N₂. Themixture was warmed to room temperature and stirred for 16 hours. Thesolution was diluted with CH₂ Cl₂ and extracted with water, 10% HCl, 10%NaHCO₃, water and brine. The solution was dried over MgSO4, and thesolvent was removed. The residue was chromatographed on silica gel,eluting with 5-10% ethyl acetate:hexane, and the solvent was removed togive 3..6 g of the title product as a white solid. MS 435 (M+H)⁺ ; ¹ HNMR (CDCl₃) δ: 0.09 (s, 6H), 0.91 (s, 9H), 1.28 (t, 3H), 1.45 (s, 9H),2.45 (dd, 1H), 2.60 (dd, 1H), 2.93 (m, 1H), 3.68 (dd, 1H), 3.78 (dd,1H), 3.84 (m, 1H), 4.15 (q, 2H), 4.52 (dd, 1H), 4.67 (dd, 1H), 4.84.

Step 413f.(S)-4-(BOC-amino)-5-(t-butyldimethylsilyloxy)-3-(aminomethyl)-pentanoicacid ethyl ester

A 4.74 g sample of the compound from step 413e above was dissolved in250 mL of ethanol and hydrogenated at 4 Atm over 14.2 g of Raney nickelcatalyst for 24 hours. The catalyst was removed by filtration and thesolvent was evaporated. The residue (mp 152°-154° C.) was taken directlyto the next step.

Step 413g.(S)-4-(1-(BOC-amino)-2-(t-butyldimethylsilyloxy)ethyl)-2-oxo-4-pyrrolidine

The residue from step 413f above was dissolved in 150 mL of ethanol andheated at reflux for 8 hours. The solvent was removed, the residue waschromatographed on silica gel, eluting with 4% methanol/methylenechloride. Removal of the solvent gave the title product.

Step 413h.(S)-4-(1-(BOC-amino)-2-(t-butyldimethylsilyloxy)ethyl)-1-benzyl-2-oxopyrrolidine

A 200 mg (0.558 mg) sample of the compound from step 413g above wasdissolved in 1 mL of THF and added dropwise to a 0° C. suspension of NaH(47 mg, 1.172 mmol) in 2 mL of THF, and the reaction mixture-was stirredfor 1 hour. To this mixture was then added 124 mg of benzyl bromide, andthe reaction was stirred at room temperature for 3 hours. The reactionwas quenched with water, and .the mixture was extracted with ethylacetate. The organic phase was acidified with citric acid solution, andthe mixture was extracted with ethyl acetate. The solvent was washedwith brine and dried over MgSO₄, filtered and evaporated. The residuewas purified by column chromatography on silica gel, eluting with 30-35%ethyl acetate:hexane, to give 168 mg of the title compound. MS 449(M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 0.03 (s, 6 H), 0.87 (s, 9H), 1.42 (s, 9H),2.26 (dd, 1H), 2.52 (dd, 1H), 2.58 (m, 1H), 3.16 (br t, 1H), 3.27 (dd,1H), 3.61 (br m, 3H), 4.28 (d, 1H), 4.59 (d, 1H), 4.70 (d, 1H), 7.23 (m,2H), 7.32 (m, 3H).

Step 413i.(S)-4-(1-(BOC-amino)-2-hydroxyethyl)-1-benzyl-2-oxopyrrolidine

A 143 mg sample of the compound from step 4 13h above was dissolved in 1mL of THF and reacted with 1 equivalent of tetra-n-butyl ammoniumfluoride at room temperature for 1.5 hours. The solvent was removed, andthe residue was dissolved in methylene chloride and purified by columnchromatography on silica gel, eluting with 5% methanol in methylenechloride, to give 110 mg of the title compound. MS 335 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ: 1.42 (s, 9H), 2.28 (m, 1H), 2.59 (m, 3H), 3.15 (m, 1H), 3.31(m, 1H), 3.61 (m, 2H), 3.70 (m, 1H), 4.30 (d, 1H), 4.58 (d, 1H), 4.78(d, 1H), 7.23 (m, 2H), 7.32 (m, 3H).

Step 413j.(S)-4-(1-(BOC-amino)-2-methoxyethyl)-1-benzyl-2-oxopyrrolidine

A sample of the compound from step 413i above (7.34 mmol) was dissolvedin 22 mL of THF and added to a suspension of 8.72 mg(16.148 mmol) ofsodium methoxide in 40 mL of THF, and the reaction mixture was stirredat room temperature under nitrogen for 1 hour. To this solution was thenadded 3.958 g of methyl iodide in 5 mL of THF, and the reaction mixturewas stirred for 16 hours. The solvents were removed under vacuum, andthe residue was dissolved in ethyl acetate, which was washed with sodiumthiosulfate and brine and dried over MgSO₄, filtered and evaporated. Theresidue was dissolved in methylene chloride and purified by columnchromatography on silica gel, eluting with 5% methanol in methylenechloride, to give the title compound. MS 349 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ:1.42 (s, 9h), 2.28 (dd, 1H), 2.56 (m, 3H), 3.14 (br t, 1H), 3.28 (dd,1H), 3.30 (s, 3H), 3.37 (d, 2H), 3.71 (br, 1H), 4.24 (dd, 1H), 4.52 (dd,1H), 4.80 (d, 1H), 7.23 (m, 2H), 7.31 (m, 3H).

Step 413k.(S)-4-(1-(BOC-amino)-2-methoxyethyl-1-benzyl-2-thioxopyrrolidine

A 50 mg (0.14 mmol) sample of the compound from step 413j above and 29mg (0.07 mmol) of Lawesson's reagent were dissolved in 0.3 mL of THF andstirred under N₂ for 3 hours. The solvent was removed, and the residuewas dissolved in CH₂ Cl₂ and chromatographed on silica gel, eluting with30% ethyl acetate:hexane. Removal of the solvent left 51 mg of product.MS 365 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 1.41 (s, 9H), 2.64 (dd, 1H), 2.87(dd, 1H), 3.16 (dd, 1H), 3.29 (s, 3H), 3.36 (d,2H), 3.55 (m, 2H), 3.70(m, 1H0, 4.70 (d, 1H), 4.83 (d, 1H), 5.21 (d, 1H), 7.33 (m, 5H).

Step 413l. (S)-3-(1-(BOC-amino)-2-methoxyethyl)-1-benzylpyrrolidine

A 45.7 mg (0.125 mmol) sample of the compound from step 413k above and239 mg (1.0 mmol) of NiCl2.6H₂ O were dissolved in 2 mL of a 1:1 mixtureof methanol and THF, and the solution was cooled to -78° C. and stirredunder N₂. A 114 mg (3.0 mmol) sample of NaBH₄ was added in portions, andthe mixture was stirred for 2 hours. The solvents were removed undervacuum, and dissolved in 20% methanol in chloroform. The solution wasfiltered and the solvent removed. The residue was chromatographed onsilica gel, eluting with 5% methanol in chloroform to provide 23 mg oftitle product. MS 335 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 1.45 (s, 9H), 2.01 (m,1H), 2.37 (m, 1H), 2.49 (m, 2H), 2.61 (m, 1H), 2.71 (m, 1H), 3.32 (s,3H), 3.35 (m, 2H), 3.44-3.67 (m, 4H), 7.23-7.33 (m, 5H).

Step 413m. (S)-3-(1-(BOC-amino)-2-methoxyethyl)-pyrrolidine

A 203 mg sample of the compound from step 413l above was dissolved in 25mL of methanol and hydrogenated at 4 Atm over 50 mg of 10% Pd/C catalystfor 22 hours. The catalyst was removed by filtration and the solvent wasevaporated to give 160 mg of the title compound as a viscous oil. MS 245(M+H)⁺ ; ¹ H NMR (CD₃ OD) δ:1.43 (s, 9H), 1.92 (m, 1H), 2.24 (m, 1H),2.43 (m, 1H), 2.75 (m, 1H), 2.90(m, 1H).

Step 413n. (3R,1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

A 77 mg (0.238 mmol) sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was reacted with the(S)-3-(1-(BOC-amino)-2-methoxyethyl)-pyrrolidine from step 4 13m aboveand carded forward as described in Example 253 steps j-l, to give 62 mgof the title product. mp. 62°-64° C. HRMS calc: 404.1986; found:404.1990 (M+H)⁺ ; ¹ H NMR (D₆ -DMSO) δ: 0.60 (m, 2H), 0.94, (m, 1H),2.13 (m, 1H), 2.28 (m, 2H), 2.61 (s, 3H), 3.26 (s, 3H), 3.52 (m, 2H),3.62 (dd, 1H), 3.71 (m, 2H), 3.91 (m, 1H), 7.91 (s, 1H), 8.10 (br, 2H),9.08 (d, 1H).

EXAMPLE 4148-(3-(S)-(acetylamino)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

To a 290 mg sample of8-(3-(S)-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid, prepared from the HCl salt of Example 257 above, suspended in 4 mLof THF was added 0.342 mL of acetic anhydride dropwise with stirring.The reaction mixture was stirred for 3.5 hours, and the precipitate wasseparated by filtration dried under vacuum to give 196 mg of the titlecompound. mp. 116°-117° C. MS 388 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 0.65 (m,1H), 0.80 (m, 1H), 1.00 (m, 1H), 1.10 (m, 1H), 2.03 (s, 3H), 2.20 (m,2H), 2.35 (m, 1H), 2.60 (s, 3H), 3.73 (m, 2H), 4.10 (m, 2H), 4.60 (m,1H), 7.48 (d, 1H, J=6 Hz), 7.75 (s, 1H), 8.83 (d, 1H, J=12 Hz), 13.95(s, 1H). Analysis calculated for C₂₀ H₂₂ FN₃ O₄.1.5 H₂ O: C, 58.60; H,6.02; N, 10.25. Found: C, 58.89; H, 5.85; N, 10.02.

EXAMPLE 4158-(3-carbamoylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Step 415a.8-(3-carbamoylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid, ethyl ester

A 971 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, prepared as in Example 253i above, was dissolved in 10mL of DMF and placed in an oven-dried system under positive N₂atmosphere. To this was added 1.15 g of nicotinamide (Aldrich) and 0.900mL of triethylamine. The reaction mixture was heated at 55° C. withstirring for 24 hours. The reaction was quenched with water, and themixture was extracted with methylene chloride. After washing with water,the organic solution was dried over Na₂ SO₄ and filtered. The solventwas removed under vacuum to give the title compound as a yellow solid(1.138 g).

Step 415b.8-(3-carbamoylpipefidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

A 442 mg sample of the compound from step 415a above was hydrolyzed withLiOH in THF/H₂ O and the title product (308 mg) was isolated asdescribed in Example 253 k. mp. 250°-251° C. MS 388 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ: 0.70 (m, 2H), 1.05 (m, 2H), 1.05 (m, 2H), 1.85 (m, 2H), 2.20(m, 2H), 2.60 (m, 1H), 2.72 (s, 3H), 3.25-3.50 (m, 4H), 3.60 (m, 1H),5.35 (s, 1H), 5.80 (s, 1H), 5.80 (s, 1H), 8.25 (s, 1H), 9.30 (d, 1H,J=14 Hz), 13.90 (s, 1H). Analysis calculated for C₂₀ H₂₂ FN₂ O₄.0.75 H₂O: C, 59.92; H, 5.91; N; 10.48. Found: C, 60.18; H, 5.89; N, 10.62.

EXAMPLE 4168-(3-hydroxypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

A 2.0 g sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, prepared as in Example 253i above, was dissolved in 25mL of DMF and placed in an oven-dried system under positive N₂atmosphere. To this was added 1.1 g of 3-hydroxypiperidine (Aldrich) and1.8 mL of triethylamine. The reaction mixture was heated at 55° C. withstirring for 144 hours. The reaction was quenched with water, and themixture was extracted with methylene chloride. After washing with water,the organic solution was dried over Na₂ SO₄ and faltered. The solventwas removed under vacuum to give the intermediate ester compound as anoil (3 g). MS 389 (M+H)⁺. This ester was purified by chromatography onsilica gel, after which the intermediate was hydrolyzed and the productisolated (1.34 g) as described in Example 415 above. mp. 232°-233° C. MS361 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ:0.70 (m, 2H), 1.03 (m, 2H), 1.75 (m, 2H),1.90 (m, 1H), 2.08 (m, 2H), 2.28 (m, 1H), 2.81 (s, 3H), 3.25 (m, 2H,J=3, 9 Hz), 3.38 (m, 2H), 3.62 (d, 1H, J=12 Hz), 3.95 (s, 1H), 4.70 (brs, 1H), 8.32 (s, 1H), 9.20 (d, 1H, J=9 Hz), 14.90 (s, 1H). Analysiscalculated for C₁₉ H₂₁ FN₂ O₄.H₂ O: C, 60.31; H, 6.13; N, 7.40. Found:C, 59.92; H, 5.79; N, 7.14.

EXAMPLE 4178-(3-hydroxymethylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

A 0.971 g sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, prepared as in Example 253i above, was dissolved in 10mL of DMF and placed in an oven-dried system under positive N₂atmosphere. To this was added 1.04 g of 3-piperidinemethanol (Aldrich)and 0.900 mL of triethylamine. The reaction mixture was heated at 55° C.with stirring for 72 hours. The reaction was quenched with water, andthe mixture was extracted with methylene chloride. After washing withwater, the organic solution was dried over Na₂ SO₄ and filtered. Thesolvent was removed under vacuum to give the intermediate ester compoundas an oil (1.25 g). MS 403 (M+H)⁺. This ester was purified bychromatography on silica gel, after which the intermediate washydrolyzed and the product isolated (785 mg) as described in Example 415above. mp. 133°-134° C. MS 375 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ:0.70 (m, 2H),1.03 (m, 2H), 1.30 (m, 1H), 1.58 (m, 2H), 1.75-2.08 (m, 3H), 2.13 (m,1H), 2.90 (s, 3H), 3.15 (m, 1H, J=l.5, 9 Hz), 3.30 (m, 1H, J=1.5, 9 Hz),3.50 (m, 1H), 3.60 (m, 1H), 3.70 (m, 2H), 8.30 (s, 1H), 9.15 (d, 1H<J=10Hz), 13.92 (s, 1H). Analysis calculated for C₂₀ H₂₃ FN₂ O₄.0.25 H₂ O: C,63.40; H, 7.39; N, 6.24. Found: C, 63.25; H, 7.29; N, 6.25.

EXAMPLE 4188-(3-(R)-hydroxypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

A 0.971 g sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, prepared as in Example 253i above, was dissolved in 10mL of DMF and placed in an oven-dried system under positive N₂atmosphere. To this was added 1.23 g of 3-(R)-(+)-hydroxypiperidine(Aldrich) and 0.900 mL of diethylamine. The reaction mixture was heatedat 55° C. with stirring for 72 hours. The reaction was quenched withwater, and the mixture was extracted with methylene chloride. Afterwashing with water, the organic solution was dried over Na₂ SO₄ andfiltered. The solvent was removed under vacuum to give the intermediateester compound as an oil (1.56 g). This ester was purified bychromatography on silica gel, after which the intermediate washydrolyzed and the product isolated (785 mg) as described in Example 415above. mp. 192°-193° C. MS 361 (M+H)³⁰ ; ¹ H NMR (CDCl₃) δ: 0.70 (m,2H), 1.02 (m, 2H), 1.75 (m, 2H), 1.90 (m, 1H), 2.05 (m, 1H), 2.28 (m,1H), 2.80 (s, 3H), 3.20 (m, 2H, J=2, 9 Hz), 3.38 (m, 2H), 3.62 (dt, 1H,J=12, 1.5 Hz), 3.90 (m, 1H), 4.60 (br s, 1H), 8.34 (s, 1H), 9.20 (d, 1H,J=10 Hz), 13.85 (s, 1H). Analysis calculated for C₁₉ H₂₁ FN₂ O₄.1.25 H₂O: C, 59.60; H, 6.19; N, 7.32. Found: C, 59.30; H, 5.94; N, 7.29.

EXAMPLE 419 (3R)-9-fluoro-3-methyl-10-(piperazin-1-yl)-2H, 3H, 6H-6-oxo-pyrano[2,3,4-ij]quinolizine-5-carboxylic acid hydrochloride

Following the procedure of Example 281f, replacing the3-(BOC-amino)pyrrolidine of that step with N-BOC-piperazine and carryingthe product forward according to steps 281g and h, the title compoundwas prepared. MS 348 (M+H)⁺ ; ¹ H NMR (DMSO-d₆) δ:12.9 (d, J=7 Hz, 3H),3.25 (m, 4H), 3.31 (m, 1H), 3.70 (m, 4H), 4.19 (dd, J=6, 11 Hz, 1H),4.37 (dd, J=4, 11 Hz, 1H), 8.03 (s, 1H), 9.04 (d, J=9 Hz, 1H), 9.12 (brs, 2H). Analysis calculated for C₁₇ H₁₈ FN₃ O₄.2.0 H₂ O: C, 48.63; H,5.52; N, 10.01. Found: C, 48.92; H, 5.57; N, 9.80.

EXAMPLE 4201-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4,3,0]nonyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 420a.6-(1-(S)-phenylethyl))-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-5,7-dione

A 10 g sample of 2,3-pyridinedicarboxylic anhydride (Aldrich) wasdissolved in 100 mL of anhydrous THF and cooled to 0° C. To thissolution was added 8.70 mL of (S)- (-)-alpha-methylbenzylamine. Thesolution was warmed to room temperature and stirred for 30 minutes, then11.96 g of 1,1'-carbonyldiimidazole was added. The reaction was stirredat room temperature under N₂ for 20 hours. The solvent was removed, andthe residue was dissolved in methylene chloride. The solvent was washedwith water and dried over MgSO₄. The solvent was removed under vacuum togive 15.344 g of the title compound.

Step 420b. 8-(1-(S)-phenylethyl-2,8-diazobicyclo[4,3,0]nonan-7,9-dione

A 15.344 g sample of the compound from step 420a above was hydrogenatedin over Pd/C in 2-methoxyethanol at 4 atm H₂ and 100° C. for 22 hours.The catalyst and solvent were removed to give 10.12 g of the titlecompound.

Step 420c. 8-((1-(S)-phenylethyl)-2,8-diazobicyclo[4,3,0]nonane

A 10.12 g sample of the compound from step 420b was dissolved in 30 mLof THF, and this solution was added dropwise to a suspension of 3.13 gof LAH in 50 mL of anhydrous THF stirred at 0° C. under N₂. Afteraddition was complete, the mixture was heated at reflux for 9 hours. Thereaction was quenched at 0° C. by sequential addition of 25 mL of H₂ O,25 mL of 15% KOH and 25 mL of H₂ O. The solids were removed byfiltration, and the filtrate was extracted with ether. The extract wasdried over MgSO₄, and the solvent was removed to give 7.98 g of thetitle compound.

Step 420d. 2-BOC-8-((1-(S)-phenylethyl)-2,8-diazobicyclo[4,3,0]nonane

A 7.98 g sample of the compound from step 40c above was dissolved in 75mL of 2:1 methanol:H₂ O. The solution was cooled to 0° C., and 7.94 g ofdi-t-butyl dicarbonate was added. The mixture was then warmed to roomtemperature and stirred for 1 hour. The organic solvent was removedunder vacuum, and the residue was slurried with methylene chloride. Theorganic phase was separated, washed and dried. The solvent was removed,and the residue was purified by chromatography on silica gel, elutingwith 100:5:0.5 methylene chloride:methanol:ammonium hydroxide, to give4.6 g of the title compound as an oil. This material was separated intothe 1,6-(R,R)- and 1,6-(S,S)-isomers by HPLC using a chiral support. TheR,R-isomer had an [α]_(D) of +31.9° C. (23°, c=1.01, methanol); TheS,S-isomer had an [α]_(D) of -84.6° C. (23°, c=1.04, methanol) (foradditional information on assignment of isomers, refer to Poster #642,ICAAC 32nd Annual Meeting, 1994).

Step 420e. (S,S)-2-BOC-2,8-diazobicyclo[4,3,0]nonane

A 1.328 g sample of the S,S-isomer from step 420d above and 1.27 g ofammonium formate were dissolved in 40 mL of methanol. The flask wasflushed with N₂, 130 mg of 10% Pd/C was added, and the reaction mixturewas heated at reflux for 1.5 hours. The solution was cooled andfiltered, then the solvent was removed. The residue was dissolved inmethylene chloride and filtered again. The solvent was removed undervacuum to give the title compound (858 mg). [α]_(D) -70.8° C. (23°,c=1.30, methanol).

Step 420f.1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4,3,0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting1,6-(S,S)-2-BOC-2,8-diazobicyclo[4,3,0]nonane from step 420e above, forthe BOC-aminopyrrolidine thereof, and carrying the product forward as insteps 253k and l, the title compound was prepared. [α]_(D) -281.3° C(23°, c=0.52, methanol). MS 386 (M-Cl)⁺ ; ¹ H NMR (DMSO-d₆) δ:0.56 (m,1H), 0.62 (m, 1H), 0.92 (m, 1H), 1.07 (m, 1H), 1.61-1.81 (m, 4H), 2.30(m, 1H), 2.56 (m, 1H), 2.67 (s, 3H), 2.92 (m, 1H), 3.25 (m, 1H), 3.69(m, 2H), 3.90 (m, 1H), 4.06 (m, 1H), 4.35 (m, 1H), 7.92 (s, 1H), 9.02(br, 1H), 9.09 (d, J=11 Hz, 1H), 9.59 (br, 1H). Analysis calculated forC₂₁ H₂₄ FN₃ O₃.HCl.1.25 H₂ O: C, 56.76; H, 6.24; N, 9.45. Found: C,56.73; H, 6.05; N, 9.44.

EXAMPLE 4211-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo-[4,3,0]nonyyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 421a. (R,R)-2-BOC-2.8-diazobicyclo[4,3,0]nonane

Following the procedure of Example 420e above, a 1.864 g sample of theR,R-isomer from Example 420d above deprotected to give 1.219 g of thetitle product. [α]_(D) +73.6° C. (23°, c=1.15, methanol). Spectral datasimilar to the compound of Example 420e was obtained.

Step 421b.1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4,3,0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting(R,R)-2-BOC-2,8-diazobicyclo[4,3,0]nonane from step 421a above, for theBOC-aminopyrrolidine thereof, and carrying the product forward as insteps 253k and l, the title compound was prepared. [α]_(D) +275.1° C(23°, c=0.53, methanol). MS 386 (M-Cl)⁺. ¹ H NMR (DMSO-d₆) δ: 0.56 (m,1H), 0.62 (m, 1H), 0.92 (m, 1H), 1.08 (m, 1H), 1.63-1.81 (m, 4H), 2.31(m, 1H), 2.56 (m, 1H), 2.68 (s, 3H), 2.91 (m, 1H), 3.25 (m, 1H), 3.69(m, 2H), 3.90 (m, 1H), 4.06 (m, 1H), 4.35 (m, 1H), 7.92 (s, 1H), 9.02(br, 1H), 9.09 (d, J=l 1 Hz, 1H), 9.60 (br, 1H). Analysis calculated forC₂₁ H₂₄ FN₃ O₃.HCl.1.5 H₂ O: C, 56.19; H, 6.29; N, 9.36. Found: C,56.19; H, 6.15; N, 9.44.

EXAMPLE 4221-cyclopropyl-8-(1-amino-3-aza-bicyclo[3,1,0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 422a.1-cyclopropyl-8-(1-BOC-amino-3-aza-bicyclo[3,1,0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid, ethyl ester

A 660 mg sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was placed in a flask, then400 mg of 1-(BOC-amino)-3-azabicyclobicyclo[3,1,0]hexane, preparedaccording to U.S. Pat. No. 5,164,402, was dissolved in 15 mL of dry THFand added to the flask. Lastly 2.2 mL of triethylamine was added, andthe solution was stirred at 5° C. for 26 hours. The reaction was cooled,quenched with 15 mL of H₂ O, and the mixture was extracted with ethylacetate. The organic extracts were dried over MgSO₄, and the solvent wasremoved under vacuum. The residue was purified by chromatography onsilica gel, eluting with 3-5% methanol in methylene chloride, to give350 mg of the title compound. MS 486 (M+H)⁺. ¹ H NMR (CDCl₃) δ: 0.61 (m,2H), 0.9-1.11 (m, 4H), 1.41 (t, J=7.5 Hz, 3H), 1.48 (s, 9H), 1.8 (br,1H), 2.19 (m, 1H), 2.62 (s, 3H), 3.59 (d, J=10.5 Hz, 1H), 3.73 (d,J=10.5 Hz, 1H), 3.8 (br, 1H), 4.0 (br, 1H), 4.4 (q, J=7.5 Hz, 2H), 5.05(br, 1H), 8.21 (s, 1H), 9.26 (d, J=10.5, 1H).

Step 422b.1-cyclopropyl-8-(1-BOC-amino-3-aza-bicyclo[3,1,0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253k, substituting the compound ofstep 422a for the starting material thereof, the title compound wasprepared. MS 458 (M+H)⁺. ¹ H NMR (CDCl₃) δ: 0.67 (m, 2H), 1.0 (m, 3H),1.1 (m, 1H), 1.48 (s, 9H), 1.82 (br, 1H), 2.22 (m, 1H), 2.68 (s, 3H),3.64 (d, J=10.5 Hz, 1H), 3.79 (d, J=10.5 Hz, 1H), 3.85 (br, 1H), 4.05(br, 1H), 5.05 (br, 1H), 8.35 (s, 1H), 9.14 (d, J=10 Hz, 1H), 13.86 (br,1H).

Step 422c.1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3,1,0]hexan-3-yl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253l, substituting the compound ofstep 422b for the starting material thereof, the title compound wasprepared. MS 358 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.62 (m, 2H), 0.98 (m,3H), 1.31 (m, 1H), 2.04 (m, 1H), 2.37 (m, 1H), 2.63 (s, 3H), 3.62 (m,1H), 3.8-4.0 (m, 3H), 8.01 (s, 1H), 8.81 (br, 2H), 9.16 (d, J=10, 1H),13.82 (br, 1H). Analysis calculated for C₁₉ H₂₁ FN₃ O₃.HCl.1.5 H₂ O: C,54.22; H, 5.75; N, 9.98. Found: C, 54.10; H, 5.61; N, 9.86.

EXAMPLE 4238-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 423a. 2-fluoromethylpropenoic acid ethyl ester

A 2.632 g (20 mmol) sample of 2-hydroxymethylpropenoic acid ethyl ester(prepared according to Villieras and Rambaud, Synthesis, 1982, 924) wasdissolved in 35 mL of methylene chloride, and the solution was cooled to-78° C. To this solution was added 2.94 mL (22 mmol) of DAST, and thereaction mixture was stirred at -78° C. for 30 minutes and at roomtemperature for 1 hour. The reaction was quenched with H₂ O (35 mL), andthe layers were separated. The organic solution was washed with brine,dried over MgSO₄, then the solvent was removed to give 2.343 g of thetitle compound. ¹ H NMR (CDCl₃) δ: 1.32 (t, J=7.5 Hz, 3H), 4.26 (q,J=7.5 Hz, 2H), 5.08 (d, J=46 Hz, 2H), 5.93 (m, 1H), 6.39 (m, 1H).

Step 423b. 1-benzyl-3-fluoromethyl-3-pyrrolidine carboxylic acid ethylester

A 739 mg (6 mmol) sample of the compound from step 423a and 1.327 g (6mmol) of N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine weredissolved in 4 mL of methylene chloride. This solution was cooled to 0°C., and 0.56 mL of 1N trifluoroacetic acid in methylene chloride wasadded slowly. The reaction mixture was stirred for 75 minutes at 0°-2°C. The solution was diluted with methylene chloride and washed withsaturated NaHCO₃ solution and water, then dried over MgSO₄. The solventwas removed, and the residue was purified by chromatography on silicagel, eluting with 4:1 hexane:ethyl acetate, to obtain 875 mg of thetitle compound. MS 266 (M+H)⁺. ¹ H NMR (CDCl₃) δ: 1.27 (t, J=7.5 Hz,3H), 1.8 (m, 1H), 2.25 (m, 1H), 2.51 (m, 1H), 2.75 (m, 3H), 3.62 (s,2H), 4.20 (q, J=7.5 Hz, 2H), 4.45 (q, J=8.7 Hz, 1H), 4.61 (q, J=8.7 Hz,1H), 7.3 (m, 5H).

Step 423c. 3-fluoromethyl-3-pyrrolidine carboxylic acid ethyl ester

A 875 mg sample of the compound from step 423b above and 1.04 g ofammonium formate were dissolved in 30 mL of ethanol. The flask wasflushed with N₂, 200 mg of Pd/C were added, and the mixture was heatedat reflux for 15 minutes. The mixture was cooled, filter, and thesolvent was removed to give 454 mg of the title compound. MS 176 (M+H)⁺.¹ H NMR (CDCl₃) δ: 1.29 (t, J=7.5, 3H), 1.8 (m, 1H), 2.15 (m, 1H), 2.95(m, 2H), 3.08 (m, 1H), 3.32 (m, 1H), 4.2 (q, J=7.5 Hz, 2H), 4.48 (m,1H), 4.63 (m, 1H).

Step 423d. 1-CBZ-3-fluoromethyl-3-pyrrolidine carboxylic acid ethylester

A 450 mg sample of the compound from step 423c above was dissolved in 4mL of 1:1 dioxane:water, 324 mg of Na₂ CO₃ was added, and the solutionwas cooled to 0° C. To this solution was added dropwise 0.44 mL ofbenzyloxycarbonyl chloride, and the reaction mixture was stirred at 0°C. for 45 minutes and at room temperature for 3 hours. The solution wasdiluted with ether, and the mixture was washed sequentially with water,saturated NaHCO₃, water and saturated brine. The ether layer wasseparated, and the solvent was removed. The residue was purified bychromatography on silica gel, eluting with 1:3 ethyl acetate:hexane togive 666 mg of the title compound. MS 3 10 (M+H)⁺. ¹ H NMR (CDCl₃) δ:1.28 (t, J=7.5 Hz, 3H), 2.05 (m, 1H), 2.32 (m, 1H), 3.55 (m, 3H), 3.84(dd, J=3, 12 Hz, 1H), 4.22 (q, J=7.5 Hz, 2H), 4.48 (m, 1H), 4.61 (m,1H), 5.14 (s, 2H), 7.35 (m, 5H).

Step 423e. 1-CBZ-3-fluoromethyl-3-pyrrolidinecarboxylic acid

A 550 mg sample of the compound from step 423d above was dissolved in 4mL of THF, and the solution was cooled to 0° C. To this solution wasadded 173 mg of LiOH and 1 mL of H₂ O. The reaction mixture was stirredat room temperature for 3 hours, then acidified by the addition of 1NHCl. The mixture was diluted with 40 mL of ethyl acetate, and the layerswere separated. The organic solution was washed with water and saturatedbrine, and the solvent was removed. The residue was purified bychromatography on silica gel, eluting with 10% methanol in methylenechloride to give 251 mg of the title compound. MS 282 (M+H)⁺. ¹ H NMR(CDCl₃) δ: 2.05 (m, 1H), 2.35 (m, 1H), 3.55 (m, 3H), 3.89 (m, 1H), 4.5(m, 1H), 4.65 (m, 1H), 5.12 (s, 1H), 7.37 (m, 5H).

Step 423f. N-BOC-1-CBZ-3-fluoromethyl-3-pyrrolidineamine

A 715 mg sample of the compound from step 423e above was dried undervacuum and dissolved in 8 mL of distilled t-butanol. To this solutionwere added 0.71 mL of triethylamine and 0.81 mL of dppa, and the mixturewas refluxed for 16 hours under a N₂ atmosphere. The reaction mixturewas cooled and diluted with ether, and the mixture was washed withwater, saturated NaHCO₃ and saturated brine. The solvent was removed,and the residue was purified by chromatography on silica gel, elutingwith 1:4 ethyl acetate:hexane to give 587 mg of the title compound. MS353 (M+H)⁺. ¹ H NMR (CDCl₃) δ: 1.44 (s, 9H), 2.1 (m, 2H), 3.55 (m, 4H),4.48 (m, 1H), 4.63 (m, 1H), 5.12 (s, 2H), 7.35 (m, 5H).

Step 423g. 3-(BOC-amino)-3-fluoromethylpyrrolidine

A 183 mg sample of the compound from step 423f above and 164 mg ofammonium formate were dissolved in 8 mL of ethanol. The flask wasflushed with N₂, 50 mg of Pd/C were added, and the mixture was heated atreflux for 20 minutes. The mixture was cooled and filtered, and thesolvent was removed to give 101 mg of the title compound. MS 219 (M+H)⁺.¹ H NMR (CDCl₃) δ: 1.45 (s, 9H), 1.6 (b, 1H), 1.92 (m, 2H), 2.95 (m,2H), 3.1 (m, 2H), 4.5 (d, J=48 Hz, 1H), 4.75 (b, 1H).

Step 423h.8-(3-(BOC-amino)-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid ethyl ester

A 120 mg (0.37 mmol) sample of8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester, from Example 253i above, was placed in a flask. To hisflask was then added a solution of 95 mg of3-(BOC-amino)-3-fluoromethylpyrrolidine, from step 423g above, dissolvedin 3 mL of DMF, and 0.30 mL of triethylamine. The reaction mixture washeated at reflux for 16 hours, then the reaction was quenched with 4 mLof water. The mixture was cooled and extracted with ethyl acetate. Theextract was dried over MgSO₄, and the solvent was removed. The residuewas purified by chromatography on silica gel, eluting with 2-5% methanolin methylene chloride, to give 143 mg of the tile compound. MS 506(M+H)⁺. ¹ H NMR (CDCl₃) δ: 0.62 (m, 2H), 0.96 (m, 2H), 1.35 (m, 1H),1.42 (t, J=7.5 Hz, 3H), 1.46 (s, 9H), 2.2 (m, 2H), 2.35 (m, 1H), 2.65(s, 3H), 3.73 (m, 1H), 3.85 (b, 1H), 3.9 (m, 1H), 4.4 (q, J=7.5 Hz, 2H),4.65 (d, J=48 Hz, 2H), 4.85 (b, 1H), 8.21 (s, 1H), 9.29 (d, J=10.5 Hz,1H).

Step 423i.8-(3-(BOC-amino)-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253k, substituting 143 mg of thecompound of step 423h for the starting material thereof, 115 mg of thetitle compound was prepared.

Step 423j.8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253l, substituting 115 mg of thecompound of step 423i for the starting material thereof, 95.5 mg of thetitle compound was prepared. MS 378 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.60(m, 2H), 1.0 (m, 2H), 2.27 (m, 2H), 2.34 (m, 1H), 2.67 (s, 3H), 3.85 (m,2H), 4.04 (m, 2H), 4.78 (d, J=46 Hz, 2H), 7.97 (s, 1H), 8.91 (b, 2H),9.13 (d, J=10.5 Hz, 1H), 13.85 (b, 1H). Analysis calculated for C₁₉ H₂₁F₂ N₃ O₃.2 HCl.0.5 H₂ O: C, 49.68; H, 5.27; N, 9.15. Found: C, 49.66; H,5.23; N, 8.91.

EXAMPLE 4248-(3-aminomethyl-3-fluoro-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253j, substituting 68 mg of3-amino-3-fluoromethylpyrrolidine, prepared as in PCT patent applicationWO9414794, for the BOC-aminopyrrolidine thereof, and carrying theproduct forward as in step 253k, the title compound was prepared (noterearrangement of positions of F and amino groups on the pyrrolidinering). MS 378 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.6 (m, 2H), 0.9 (m, 1H),1.05 (m, 1H), 1.25 (m, 1H), 2.2-2.5 (m, 2H), 2.64 (s, 3H), 3.4 (m, 2H),3.81 (m, 2H), 4.15 (m, 2H), 7.95 (s, 1H), 8.4 (b, 2H), 9.1 (d, J=10.5Hz, 1H), 10.2 (s, 1H).

EXAMPLE 4258-(3-(S)-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Step 425a. (S)-1-BOC-3-pyrrolidinol

A 9.8 g (55.2 mmol) sample of (S)-1-benzyl-3-pyrrolidinol was dissolvedin 200 mL of ethanol, 1.96 g of 20% Pd/C was added, and the mixture wasstirred under N₂. To this mixture was added 17.4 g of ammonium formate,and the reaction mixture was stirred for 10 minutes at an internaltemperature of 70° C. The reaction mixture was removed for the bath andcooled until gas evolution subsided. The mixture was cooled, thendiluted with methylene chloride. The solids were removed by filtration,and the filtrate was concentrated. The residue was suspended in 200 mLof methylene chloride, and 2.07 g of di-t-butyl dicarbonate was addedwith stirring and while holding the temperature at 19°-23° C. Themixture was stirred at room temperature for 16 hours. The organicsolvent was removed under vacuum, and the residue was slurried withmethylene chloride. The organic phase was separated, washed and dried.The solvent was removed, and the residue was purified by chromatographyon silica gel to give 8.94 g of the title compound as a colorless oil.

Step 425a.8-(3-(S)-hydroxy-1-pyrrolidinyl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253j, substituting(S)-1-BOC-3-pyrrolidinol, from step 425a above, for theBOC-aminopyrrolidine thereof, and carrying the product forward as instep 253k, the title compound was prepared. mp. 240° C. MS 347 (M+H)⁺. ¹H NMR (DMSO-d₆) δ: 0.6 (m, 2H), 0.95 (m, 1H), 1.05 (m, 1H), 2.0 (m, 2H),2.3 (m, 1H), 2.6 (s, 3H), 3.4 (d, 1H), 3.7 (m, 1H), 4.0 (m, 2H), 4.4 (brs, 1H), 5.65 (d, 1H), 7.9 (s, 1H), 9.05 (d, 1H), 18.5 (s, 1H).Analysis-calculated for C₁₈ H₁₉ FN₂ O₄ : C, 62.42; H, 5.53; N, 8.09.Found: C, 62.34; H, 5.38; N, 7.99.

EXAMPLE 4268-(3,(R)-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedures of Example 425, replacing the(S)-1-benzyl-3-pyrrolidinol with (R)-1-benzyl-3-pyrrolidinol, the titlecompound was prepared. mp. 240° C. MS 347 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ:0.6 (m, 2H), 0.95 (m, 1H), 1.05 (m, 1H), 2.0 (m, 2H), 2.3 (m, 1H), 2.6(s, 3H), 3.4 (d, 1H), 3.7 (m, 1H), 4.05 (m, 2H), 4.45 (br s, 1H), 5.65(d, 1H), 7.9 (s, 1H), 9.05 (d, 1H), 18.5 (s, 1H). Analysis calculatedfor C₁₈ H₁₉ FN₂ O₄ : C, 62.42; H, 5.53; N, 8.09. Found: C, 62.54; H,5.56; N, 7.96.

EXAMPLE 4278-(1-amino-5-aza-spiro[2,4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride Diasteromer A

Step 427a. (5-(benzyl-amino)-5-aza-1-spiro[2,4]heptane acetic acid ethylester

A 1.36 g (34 mmol) sample of Nail was suspended in 42 mL of stirredhexane. The hexane was then decanted to remove the mineral oil. To theresidue was added 34 mL of DMSO and 7.9 g of trimethylsulfoxonium iodidein portions. The reaction was stirred at room temperature for 30minutes, during which H₂ gas was released. To this mixture was thenadded 10 mL of DMSO containing 4.19 g (17 mmol) of1-benzyl-3-ethoxycarbonylmethylenepyrrolidine, prepared as described inpublished European Application EP550016, and the reaction mixture wasstirred for 1 hour at room temperature and 2 hours at 55° C. Thereaction was quenched with 350 mL of water, and the mixture wasextracted with methylene chloride. The extract was washed with water andbrine, then dried, and the solvent was removed. The residue waschromatographed on silica gel, eluting with 22:88 ethyl acetate:hexane,which resolved and separated the two chiral diastereomers, which weredesignated as Diastereomers A and B.

Step 427b. (5-(BOC-amino)-5-aza-1-spiro[2,4]heptane acetic acid ethylester and (R)-(5-(BOC-amino)-5-aza-1-spiro[2,4]heptane acetic acid ethylester

A 1.18 g sample of Diastereomer A from step 427a was dissolved in 25 mLof ethanol, and 240 mg of 20% Pd(OH)2/C and 1.1 g of di-t-butyldicarbonate were added. The mixture was stirred under H₂ at roomtemperature for 23 hours, then filtered. The solvent was removed, andthe residue was purified on silica gel, eluting with 15:85 ethylacetate:hexane. MS 347 (M+H)⁺.

Step 427c. (5-(BOC-amino)-5-aza-1-spiro[2,4]heptane acetic acid

A 0.49 g sample of the compound from step 427b above was dissolved in 4mL of methanol, and 180 mg of NaOH in 2 mL of water was added. Themixture was stirred at room temperature for 3 hours, and the solvent wasremoved. Additional water was added and the solution was acidified with2.3 mL of 2N HCl. The solution was extracted with methylene chloride,and the extract was dried and evaporated. The residue was 332 mg of aheavy oil, which was dried and taken to the next step.

Step 427d.1-(bcnzyloxycarbonylamino-(5-(BOC-amino)-5-aza-spiro[2,4]heptane

A 1.455 g (6.03 mmol) sample of the compound from step 427c above, 30 mLof dioxane, 1.5 mL of DPPA, 0.9 mL of triethylamine and 1.0 mL of drybenzyl alcohol were placed in a flask, and the mixture was heated at100° C. for 2 hours, at 110° C. for 17 hours and at 120° C. for 17hours. The solvent was evaporated, and the residue was dissolved inmethylene chloride. The solution was washed with NaHCO₃ solution, andthe organic layer was washed, dried and evaporated. The residue waschromatographed on silica gel, eluting with 35:65 ethyl acetate:hexane,and an oil was obtained. MS 347 (M+H)⁺.

Step 427e. 5-amino-1-(benzyloxycarbonyl)amino-5-aza-spiro[2,4]heptane

A 541 mg sample of the compound from step 427d was dissolved in 10 mL ofanhydrous ethyl acetate, and 2.35 mL of 4M HCl in dioxane was added. Thesolution was stirred at room temperature for 24 hours. The solvent wasremoved, and the residue was triturated with 31.6 mL of 5% NaHCO₃solution. The mixture was extracted with methylene chloride, thenextracted with a 1:3 methanol:methylene chloride mixture. The extractwas washed with brine and dried. The solvent was removed to give 0.384 gof the title compound, which was taken directly to the next step.

Step 427f.8-(1-(benzyloxycarbonyl)amino-5-aza-spiro[2,4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253j, substituting the compound fromstep 427e above, for the BOC-aminopyrrolidine thereof, and carrying theproduct forward as in step 253k, the title compound was prepared.

Step 427 g.8-(1-amino-5-aza-spiro[2,4]heptan-5-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride Diastereomer A

A 355 mg sample of the compound from step 427f was dissolved in amixture of 20 mL of methanol and 8 mL of methylene chloride. To this wasadded 2 mL of formic acid, then the flask was flushed with N₂ and 142 mgof 10% Pd/C was added. The mixture was stirred at room temperature for30 minutes. The mixture was diluted and filtered, and the filtrate wasconcentrated. The residue was dissolved in 2 mL of methanol, and 1.5 mLof 1N HCl in ether was added. Next 100 mL of ether was added, and thetitle compound was collected by filtration and dried. mp. 200° C. (dec).MS 372 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.6 (d, 2H), 1.0 (dd, 2H), 1.15 (t,2H), 1.9 (m, 1H), 2.05 (m, 1H), 2.3 (m, 1H), 2.65 (s, 3H), 2.75 (m, 1H),3.75 (m, 1H), 3.8 (m, 1H), 4.0 (m, 2H), 7.9 (s, 1H), 8.5 (br s, 2H), 9.1(d, 1H). Analysis calculated for C₂₀ H₂₂ FN₃ O₃.HCl.2 H₂ O: C, 54.12; H,6.13; N, 9.47. Found: C, 54.47; H, 5.79; N, 9.45.

EXAMPLE 4288-(1-amino-5-aza-spiro[2,4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride Diastereomer B

Following the procedures of Example 427b, substituting the DiastereomerB (5-(BOC-amino)-5-aza-1-spiro[2.4]heptane acetic acid ethyl ester, fromstep 427a, for the A isomer thereof, and carrying the product forward asin steps 427c-g, the title compound was prepared. mp. 200° C. (dec). MS372 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.6 (d, 2H), 1.0 (t, 2H), 1.1 (t,2H),1.15 (t, 1H), 2.15 (m, 2H), 2.3 (m, 1H), 2.6 (s, 3H), 2.8 (br m,1H), 3.65 (m, 1H), 3.8 (m, 2H), 4.15 (m, 1H), 7.9 (s, 1H), 8.6 (br s,2H), 9.1 (d, 1H) 13.85 (br s, 1H). Analysis calculated for C₂₀ H₂₂ FN₃O₃.HCl.2 H₂ O: C, 54.12; H, 6.13; N, 9.47. Found: C, 54.21; H, 5.85; N,9.38.

EXAMPLE 4298-(3-(R*)-(1-(S*)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 429a.1-benzyl-3-(1-hydroxy-2,2,2-trifluoroethylidene)-2-pyrrolidone

A 1.2 g sample of NaH was suspended in 30 mL of dry THF, and thissuspension was stirred at room temperature. To this was added 3.5 g of1-benzyl-2-pyrrolidone (Aldrich), and the mixture was stirred at 65° C.To this mixture was next added 3.6 mL of ethyl trifluoroacetate in 10 mLof THF over a 25 minute period, and the reaction was heated at refluxfor 3 hours. The reaction mixture was cooled, diluted with ether andneutralized with 1N HCl. The ether layer was separated, washed withbrine, dried and taken to dryness. The residual oil was chromatographedon silica gel, eluting with 1:1 ethyl acetate:hexane to give 2.06 g ofthe title compound. MS 289 (M+H)⁺.

Step 429b.1-benzyl-3-(1-hydroxylimino-2,2,2-trifluoroethyl)-2-pyrrolidone

A 2.0 g sample of the compound from step 429a, 7.6 g of hydroxylamineHCl, 20 mL of pyridine and 40 mL of ethanol was heated at reflux for 4hours. The solvents were removed under vacuum, and the residue wasdissolved in methylene chloride. The solution was washed with water andbrine, then dried and the solvent evaporated. The residue wasazeotropically distilled with toluene to remove the pyridine to giveafter drying 1.30 g of title compound. MS 287 (M+H)⁺.

Step 429c. 1-benzyl-3-(1-amino-2,2,2-trifluoroethyl)-2-pyrrolidine

A 1.3 g sample of the compound from step 429c was dissolved in 20 mL ofTHF, and 10 mL of 1M LAH in THF was added. The mixture was heated atreflux for 4 hours. The reaction was quenched while stirring under a N₂atmosphere by the sequential addition of 0.4 mL H₂ O, 0.4 mL of 15% NaOHand 1.2 mL of H₂ O. The suspension was filtered, and the filtrate waswashed with brine, dried and evaporated. The residue was then purifiedby chromatography on silica gel, eluting with 5:95 methanol:methylenechloride to give 943 mg of title compound. MS 259 (M+H)⁺.

Step 429d. 1-benzyl-3-(1-(BOC-amino)-2,2,2-trifluoroethyl-2-pyrrolidine

A 0.94 g sample of the compound from step 429c was dissolved in 5 mL ofmethylene chloride, and 0.8 g of di-t-butyl dicarbonate in 1 mL ofmethylene chloride was added. The mixture was stirred at roomtemperature for 16 hours. Another 0.4 g of di-t-butyl dicarbonate wasthen added, and the reaction was stirred for 24 hours. The solvent wasremoved, and the residue was chromatographed on silica gel, eluting with25:75 ethyl acetate :hexane. The product was resolved into twodiastereomers by chromatography (they were arbitrarily assigned therelative stereochemistry 1S*,3R* and 1S*,3S*). Carrying the 1S*,3R*compound forward the title compound was prepared.

Step 429e. 3-(1-(BOC-amino)-2,2,2-trifluoroethyl)-2-pyrrolidine

A 1.49 g sample of the compound from step 429d was dissolved in 100 mLof methanol, 0.9 g of 10% Pd/C was added, and the mixture washydrogenated under 4 atm of H₂ for 44 hours. The mixture was filtered,the filtrate was concentrated. The residue was triturated withacetonitrile, then filtered. The filtrate was concentrated to give 1.035g of the title compound. MS 269 (M+H)⁺.

Step 429f.8-(3-(R*)-(1-(S*)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting the compound fromstep 429e above, for the BOC-aminopyrrolidine thereof, and carrying theproduct forward as in step 253k, then removing the BOC-group byhydrolysis as in Example 253l, with 1N HCl in acetic acid. mp browned160°-163° C., decomposed at 180°-183° C. MS 428 (M+H)⁺. ¹ H NMR(DMSO-d₆) δ:0.6 (d, 2H), 0.9 (m, 1H), 1.1 (m, 1H), 1.9 (m, 1H), 2.3 (m,1H), 2.6 (s, 3H), 2.75 (m, 1H), 3.7 (m, 2H), 4.0 (m, 2H), 4.4 (m, 1H),7.9 (s, 1H), 9.1 (d, 1H), Analysis calculated for C₂₀ H₂₁ F₄ N₃ O₃.HCl.2H₂ O: C,48.05; H, 5.24; N, 8.41. Found: C, 48.45; H, 5.20; N, 8.50.

EXAMPLE 4308-(3-(S*)-(1-(S*)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Carrying the 1S*,3S* compound from Example 429d above forward as inExamples 429e and 253j, k and l the title compound was prepared. mpbrowned 205° C., melted at 213° C. MS 428 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ:0.6 (d, 2H), 1.0 (m, 2H), 2.0 (m, 1H), 2.3 (m, 1H), 2.65 (s, 3H), 2.75(m, 1H), 3.75 (m, 2H), 4.0 (m, 2H), 4.4 (m, 1H), 7.9 (s, 1H), 9.1 (d,1H). Analysis calculated for C₂₀ H₂₁ F₄ N₃ O₃.HCl.2.5 H₂ O: C,47.20; H,5.34; N, 8.26. Found: C, 47.14; H, 4.91; N, 8.55.

EXAMPLE 4318-(3-aminoxypyrrolidinyl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 431a. 1-BOC-3-pyrrolidinol

To a solution of 3.25 g of 3-pyrrolidinol in 25 mL of methylene chloridewas added, with cooling, 5 mL of methylene chloride containing 8.2 g ofdi-t-butyl dicarbonate, and the mixture was stirred for 4 hours. Thevolatiles were removed under vacuum, and the residue was chromatographedon silica gel, eluting with 7 % methanol in methylene chloride to give7.64 g of the title compound.

Step431b. N-(1-BOC-3-pyrrolidinoxy)phthalimide

To 50 mL of dry THF were added 5.17 g of the compound from 431a above,9.7 g of triphenylphosphine, and 5.41 g of N-hydroxyphtahalimide. Tothis suspension, stirred and cooled to -20° C., was added 5.83 mL ofDEAD, and the mixture was stirred for 1 hour at -20° C. The solution wasquenched with water, then extracted with methylene chloride. The organiclayer was dried and concentrated. The residue was chromatographed onsilica gel, eluting with 40:60 ethyl acetate:hexane to give 7.60 g ofthe title compound.

Step 431c. (1-B OC-3-pyrrolidinoxy)amine

To a solution of 7.4 g of the compound from step 431b in 100 mL ofmethylene chloride was added 2.6 mL of hydrazine hydrate. The mixturewas stirred at room temperature for 1 hour. The precipitate was removedby filtration, and the filtrate was washed with water, dried andevaporated to give 4.325 g of the title product as an oil.

Step 431d. 3-pyrrolidinoxyamine

A 4.318 g sample of the compound from step 431c was dissolved in 70 mLof dry methylene chloride, and 70 mL of 1M HCl in acetic acid was added.The mixture was stirred for 30 minutes at room temperature. Theprecipitate was collected by filtration, washed and dried to give 3.41 gof the tile compound.

Step 431e.8-(3-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid ethyl ester

A 0.25 g sample of the 3-pyrrolidinoxyamine from step 431d above and1.06 mL of triethylamine were dissolved in 5 mL of dry THF, and themixture was stirred at 55° C. for 7 hours. The reaction was quenchedwith water, and the mixture was extracted with ethyl acetate. Theorganic layer, wash washed with water, dried and evaporated. The residuewas chromatographed on silica gel, eluting with 100:7;0.7 methylenechloride:methanol:NH4OH to give 224 mg of the title compound.

Step 431f.8-(3-(BOC-aminoxy)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid ethyl ester

A mixture of 224 mg of the compound from step 431e and 0.25 g ofdi-t-butyl dicarbonate were dissolved in 3 mL of methylene chloride, andthe mixture was stirred for 4 days. The volatiles were removed, and theresidue was taken directly to the next step.

Step 431g.8-(3-(BOC-aminoxy)pyrrolidinyl)-1-Cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine4-carboxylicacid

The material from the previous step, 4 mL of THF, 3 mL of water, 0.216 gof LiOH were combined, and the mixture was heated at 83° C. for 3 hours.The mixture was acidified with 1N HCl, and the precipitate was removedby filtration. The filtrate was washed with water and brine, thenevaporated to give 245 mg of the title compound.

Step 431h.8-(3-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

A 200 mg sample of the compound from step 431g was dissolved in 23 mL ofdry methylene chloride and treated with 1N HCl in acetic acid at roomtemperature for 16 hours. The title compound was collected byfiltration, washed with methylene chloride and dried. mp -158°-161° C.(dec). MS 362 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.6 (d, 2H), 0.9, (m, 1H),1.05 (m, 1H), 2.3 (m, 3H), 2.6 (s, 3H), 3.65 (m, 1H), 3.75 (m, 1H), 4.0(m, 1H), 4.2 (m, 1H), 5.0 (br s, 1H), 7.9 (s, 1H), 9.1 (d, 1H), 11.1 (brs, 2H). Analysis calculated for C₁₈ H₂₀ FN₃ O₄.HCl.H₂ O: C, 51.99; H,5.57; N, 10.10. Found: C, 51.84; H, 5.33; N, 9.95.

EXAMPLE 4328-(3-(R)-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedures of Example 432, except substituting(S)-1-BOC-3-pyrrolidinol for the racemic starting material thereof, thetitle compound was prepared. mp 160°-168° C. (dec). MS 362 (M+H)⁺. ¹ HNMR (DMSO-d₆) δ: 0.6 (d, 2H), 0.9, (m, 1H), 1.05 (m, 1H), 2.3 (m, 3H),2.6 (s, 3H), 3.65 (m, 1H), 3.8 (m, 1H), 4.0 (m, 1H), 4.15 (m, 1H), 4.95(br s, 1H), 7.95 (s, 1H), 9.1 (d, 1H), 10.7 (br s, 2H). Analysiscalculated for C₁₈ H₂₀ FN₃ O₄.HCl.0.75 H₂ O: C, 52.56; H, 5.51; N,10.22. Found: C, 52.91; H, 5.57; N, 10.14.

EXAMPLE 4338-(3-(S)-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedures of Example 432, except substituting(R)-1-BOC-3-pyrrolidinol for the racemic starting material thereof, thetitle compound was prepared. mp 160°-168° C. (dec). MS 362 (M+H)⁺. ¹ HNMR (DMSO-d₆) δ: 0.6 (d, 2H), 0.9, (m, 1H), 1.0 (m, 1H), 2.3 (m, 3H),2.6 (s, 3H), 3.65 (m, 1H), 3.85 (br d, 1H), 4.0 (m, 1H), 4.15 (m, 1H),4.95 (br s, 1H), 7.9 (s, 1H), 9.1 (d, 1H), 10.9 (br s, 2H). Analysiscalculated for C₁₈ H₂₀ FN₃ O₄.HCl.0.75 H₂ O : C, 52.56; H, 5.51; N,10.22. Found: C, 52.98; H, 5.51; N, 10.16.

EXAMPLE 4348-(octahydropyrrolo[3,2-b]pyridin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 434a. 3-nitro-2-pyridineacetic acid ethyl ester

A mixture of 25 g sample of diethyl malonate and 3 g of sodium wasstirred at room temperature until the reaction was complete, thenstirred at 120° C. for 30 minutes. The mixture became a thicksuspension, and 50 mL of toluene was added, followed by 17.17 g of2-chloro-3-nitropyridine. The mixture was heated at reflux for 16 hours.The solvents were removed under vacuum, and the residue was dissolved in50 mL of DMSO. To this solution was added 19.5 g of NaCl and 7.2 g ofwater, and the mixture was stirred at 160°-170° C. for 3 hours. Themixture was cooled and diluted with ethyl acetate. The layers wereseparated, and the organic layer was washed with water, brine and driedover MgSO₄. The solvent was removed, and the residue was chromatographedon silica gel to give 11.3 g of the title compound. ¹ H NMR (CDCl₃) δ:8.8 (dd, 1H), 8.45 (dd, 1H), 7.5 (dd, 1H), 6.35 (s, 2H), 4.15 (q, 2H),1.25 (t, 3H).

Step 434b. 1,3-dihydropyrrolo[3,2-b]pyridin-2-one

A 6 g sample of the compound from step 434a was dissolved in ethanol andhydrogenated at 4 atm over Pd/C for 2 hours. The mixture was filtered,and the filtrate was evaporated to give the 3-amino compound. Thisintermediate was dissolved in 60 mL of 2N HCl, and the solution washeated at reflux for 30 minutes. The mixture was neutralized with K₂ CO3to pH7-8, and the mixture was extracted with 4:1 methylenechloride:i-propanol. The extract was dried, and the solvent was removedto give the title compound. ¹ H NMR (CDCl₃) δ: 8.05 (m, 1H), 7.12 (m,2H), 3.55 (s, 2H).

Step 434c. 4-(BOC-amino)-octahydropyrrolo[3,2-b]pyridin-2-one

A 2.8 g sample of the compound from step 434b was dissolved in 150 mL ofacetic acid, and 1 g of PtO2 was added. The mixture was hydrogenated at60 psi for 24 hours and at 2000 psi for 2 hours. The mixture wasfiltered, and the solvent was removed. The residue was dissolved in 10mL of methanol, and 3 g NaHCO₃, 5 mL of water and 6 g of di-t-butyldicarbonate were added sequentially. The mixture was stirred at roomtemperature for 4 hours. The mixture was diluted with methylenechloride, and the mixture was washed with water and brine. The solventwas dried and evaporated, and the residue was purified by chromatographyon silica gel, eluting with 7:100 methanol:methylene chloride to give3.1 g of the title compound.

Step 434d. 4-(BOC-amino)-octahydropyrrolo[3,2-b]pyridine

A 3.1 g sample of the compound from step 434c was dissolved in 20 mL ofTHF and heated with 2.6 g of Lawesson's Reagent at reflux for 2.5 hours.The solvent was removed, and the residue was chromatographed on silicagel. The intermediate product thus obtained was dissolved in 40 mL ofmethanol, and 30 g of 50% Raney Ni in water was added. The mixture wasstirred at room temperature for 30 minutes, then filtered. The solventwas removed to give 2.5 g of the title compound. ¹ H NMR (CDCl₃) δ:4.6-4.5 (m, 1H), 4.40 (m, 1H), 2.95-3.10 (m, 2H), 2.65-2.75 (m, 1H),1.90-2.0 (m, 1H), 1.60-1.70 (m, 4H), 1.45 (s, 9H), 1.30-1.40 (m, 2H).

Step 434e.8-(octahydropyrrolo[3,2-b]pyridin-1-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting the4-(BOC-amino)-octahydropyrrolo[3,2-b]pyridine from step 434d for theBOC-amino-pyrrolidine thereof, and carrying the product forward as insteps 253k & l, the title compound was prepared. MS 386 (M+H)⁺. ¹ H NMR(DMSO-d₆) δ: 9.20 (d, 1H), 8.0 (s, 1H), 4.5 (m, 1H), 4.40 (m, 1H), 3.95(m, 1H), 3.20 (m, 1H), 2.90 (m, 1H), 2.70 (s, 3H), 2.4-2.6 (m, 3H), 2.10(m, 1H), 1.90 (m, 2H), 1.50 (m, 2H), 0.9-1.10 (m, 2H), 0.60 (m, 2H).

EXAMPLE 4358-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 435a. 4-fluoro-2-butenoic acid ethyl ester

A 1.6 g sample of ethyl fluoroacetate was dissolved in methylenechloride, and the mixture was cooled to -78° C. To this solution wasadded 1 equivalent of DIBAL (1.0M in methylene chloride) during a 30minute period. The reaction mixture was stirred for another 30 minutes,then the reaction mixture was warmed to room temperature and 1.1equivalent of (triphenylphosphoran)ilidenylethyl acetate was added. Thereaction mixture was stirred for 16 hours. The reaction was quenched byaddition of methanol, and 5% citric acid solution. The mixture wasextracted with methylene chloride, and the extract was dried andevaporated. The residue was distilled to yield a 3:1 mixture of thecis:trans isomers of the title compound.

Step 435b. 1-benzyl-3-fluoromethyl-2-pyrrolidineacetic acid ethyl ester

The compound (2.6 g, 20 mmol) from step 435a and 5 g ofN-benzyl-N-(methoxymethyl)trimethylsilylamine were dissolved in 30 mL ofdry methylene chloride. The solution was stirred at 0° C., and 1%trifluoroacetic acid was added dropwise. The mixture was then stirredfor 1.5 hours at room temperature. The solvent was removed, and theresidue chromatographed on silica gel to give cis- and trans isomers ofthe title compound.

Step 435c. trans-1-CBZ-3-fluoromethyl-2-pyrrolidineacetic acid ethylester

The trans compound from step 435b was dissolved in 20 mL of ethanol, and10 equivalents of ammonium formate and 170 mg of 10% Pd/C. The reactionmixture was heated at reflux and stirred for 30 minutes. The mixture wasfiltered, and the filtrate was evaporated. The residue was dissolved in10 mL of dioxane and 2.5 mL of water, and 20% Na₂ CO₃ was added. Themixture was cooled to 0° C., and 1.5 equivalents of benzoyloxycarbonylchloride was added slowly. The reaction was stirred for 30 minutes, thendiluted with 100 mL of ether. The organic layer was separated, washedwith brine and dried over MgSO₄. The solvent was removed, and theresidue was chromatographed on silica gel to give 1.5 g of the titlecompound. ¹ H NMR (CDCl₃) δ:7.3-7.4 (m, 5H), 5.12 (s, 2H), 4.60 (m, 1H),4.10-4.20 (q, 2H), 3.60-3.90 (m, 3H), 3.30-3.40 (m, 1H), 2.7-3.05 (m,2H), 1.25 (t, 3H).

Step 435d. trans-2-(BOC-amino)-1-CBZ-3-fluoromethyl-pyrrolidine

A 1.5 g sample of the compound from step 435c was dissolved in 12 mL ofTHF. The solution was cooled to 0° C., and 4 equivalents of LiOH in 3 mLof water were added. The mixture was stirred a 0° C. for 2 hours, thendiluted with water and acidified with 2N HCl to pH 2. The mixture wasextracted with ether, and the extract was washed with brine and dried.The solvent was removed, and the residue was chromatographed on silicagel to give the intermediate acid. This compound was dissolved in 10 mLof anhydrous THF, and 1.1 equivalent of DPPA and 4 equivalents oftriethylamine were added. The mixture was heated at reflux for 24 hours,then cooled. The solvent was removed, and the residue waschromatographed on silica gel. ¹ H NMR (CDCl₃) δ: 7.3-7.4 (m, 5H), 5.12(s, 2H), 6.4-4.60 (m, 3H), 4.05-4.10 (m, 1H), 3.80-3.90 (m, 1H),3.65-3.75 (m, 1H), 3.30-3.40 (m, 1H), 3.20 (m, 1H), 2.40-2.50 (m, 1H),1.95 (s, 9H).

Step 435e. trans-2-(BOC-amino)-3-fluoromethyl-pyrrolidine

The compound from step 435d was hydrogenated with Pd/C in NMF andethanol as in step 435c above, and the title compound was isolated.

Step 435f.8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting thetrans-2-(BOC-amino)-3-fluoromethyl-pyrrolidine from step 435e for theBOC-amino-pyrrolidine thereof, and carrying the product forward as insteps 253k & l, the title compound was prepared. MS 378 (M+H)⁺. ¹ H NMR(DMSO-d₆) δ: 9.12 (d, 1H), 7.95 (s, 1H), 4.70-4.80 (m, 1H), 4.55-4.65(m, 1H), 3.6-4.15 (m, 5H), 2.8-3.0 (m, 1H), 2.65 (s, 3H), 2.3-2.4 (m,1H), 1.0 (m, 2H), 0.60 (m, 2H).

EXAMPLE 4368-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 435c, replacing the trans-isomer withthe cis-isomer from step 435b, and carrying the product forward as insteps 435d-f, the title compound was prepared.

EXAMPLE 4378-(8-amino-6-azaspiro[3,4]oct-6-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4oxo-quinolizine-3-carboxylicacid hydrochloride

Step 437a. cyclobutylideneacetic acid ethyl ester

A 5 g sample of cyclobutanone was mixed with 1.1 equivalent of(carboethhoxymethyl)triphenylphosphorane in 20 mL of toluene. Themixture was heated at reflux for 16 hours, then faltered, and thefiltrate was distilled, with the title compound distilling at 186°-188°C.

Step 437b.8-(8-amino-6-azaspiro[3,4]oct-6-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedures of Example 435b, replacing the compound of step435a with the cyclobutylideneacetic acid ethyl ester from step 437aabove, and carrying the product forward according to steps 435c-f, thetitle compound was prepared. MS .386 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 9.10(d, 1H), 7.92 (s, 1H), 6.1-4.25 (m, 2H), 3.9 (m, 1H), 3.65-3.80 (m, 2H),2.62 (s, 3H), 2.25-2.40 (m, 1H), 1.85-2.20 (m, 3H), 0.9-1.1 (m, 2H), 0.6(m, 2H).

EXAMPLE 4388-(2-(R)-aminomethyl-4-(R)-hydroxypyrrolidin-1-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 438a.N-((1-BOC-4-(R)-(tributylsilyloxy)pyrrolidinyl)methyl)phthalimide

A 4.5 g (14 mmol) sample of1-BOC-2-(R)-hydroxymethyl-4-(R)-(tributylsilyloxy)pyrrolidine, 2.50 g(17 mmol) of phthalimide and 4.46 g (17 mmol) of triphenylphosphine weredissolved in 30 mL of THF at room temperature. To this solution wasadded 2.94 g (17 mmol) of DEAD in THF dropwise, and the mixture wasstirred for 3 hours. The solvent was removed under vacuum, and theresidue was dissolved in 1:1 ether:ethyl acetate. The solution waswashed with water and brine and dried over MgSO₄. The solvent wasremoved, and the residue was chromatographed on silica gel to give thetitle compound.

Step 438b. N-((1-BOC-4-(R)-hydroxypyrrolidinyl)methylphthalimide

A 4.60 g sample of the compound from step 438a was dissolved in 20 mL ofTHF. Tetrabutylammonium fluoride (1M in THF) was added dropwise whilemaintaining the solution at 0° C., the reaction was stirred at roomtemperature for 30 minutes. The mixture was diluted with ethyl acetate,then washed with water, brine and dried. The solvent was removed to givethe title compound.

Step 438c. N-((4-(R)-hydroxypyrrolidinyl)methyl)phthalimide

A 2 g sample of the compound from step 438b was dissolved in 10 mL ofmethylene chloride, and 4N HCl in dioxane was added. The mixture wasstirred for 4 hours, and the product was collected by filtration.

Step 438d. N-((1-CBZ-4-(R)-hydroxypyrrolidinyl)methyl)phthalimide

The compound from step 438c was dissolved in 10 mL of dioxane, and 3 gof Na₂ CO₃ was added. The mixture was stirred at 0° C. for 30 minutes,then 1.1 equivalent of benzyl chloroformate was added dropwise. Thereaction was stirred for 1 hour, and ethyl acetate was added. The waterlayer was separated, and the organic layer was washed and dried. Thesolvent was removed to give the title compound.

Step 438e. 2-(R)-aminomethyl-1-CBZ-4-(R)-hydroxypyrrolidine

The compound from step 438d was dissolved in 20 mL of ethanol, and 1.2equivalents of hydrazine hydrate was added. The mixture was heated atreflux for 2 hours, 6N HCl was added, and the mixture was filtered. Thefiltrate was concentrated to give the title compound.

Step 438f. 2-(R)-(BOC-amino)methyl-1-CBZ-4-(R)-hydroxypyrrolidine

The compound of step 438e was treated with di-t-butyl dicarbonate andNaHCO₃ in methanol/water as described above, to give the title compound.

Step 438g. 2-(R)-(BOC-amino)methyl-4-(R)-hydroxypyrrolidine

The compound of step 438f was treated with ammonium formate and Pd/Cusing the procedure described above to five the title compound.

Step 438h.8-(2-(R)-aminomethyl-4-(R)-hydroxypyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedures of Example 435b, replacing the compound of step435a with the 2-(BOC-amino)methyl-4-hydroxypyrrolidine from step 438gabove, and carrying the product forward according to steps 435c-f, thetitle compound was prepared. MS 376 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 9.20(d, 1H), 8.0 (s, 1H), 5.58 (m, 1H), 4.60 (m, 1H), 4.40 (m, 1H), 3.88 (m,1H), 2.95 (m, 2H), 2.70 (s, 3H), 2.40 (m, 2H), 1.90 (m, 1H), 0.90-1.10(m, 2H), 0.60 (m, 2H).

EXAMPLE 4398-(3-(R)-(aminomethyl)morpholin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 439a. 1-benzyl-3-(R)chloromethyl)morpholine

A 1.53 mL (10.8 mmol) sample of N-benzylethanolamine and 5.0 g (54 mmol)of (R)-(-)-epichlorohydrin were combined and heated at 40° C. for 40minutes, then the excess epichlorohydrin was removed by distillation.The residue was dissolved in 2 mL of conc. H₂ SO4, and the mixture washeated at 140° C. for 35 minutes. The reaction was quenched by pouringit onto ice, and the pH was adjusted with 20% NaOH to pH 10-12. Themixture was extracted with methylene chloride, and the solvent wasdried, filtered and concentrated to give the title compound (0.97 1 g).MS 226 (M+H)⁺.

Step 439b. (R)-N-((1-benzylmorpholin-3-yl)methylphthalimide

A 971 mg sample of the compound from step 439a was dissolved in 20 mL ofDMSO and 1.59 g of phthalimide was added. The reaction mixture washeated at 100° C. for 72 hours. The reaction was quenched by pouring itinto 250 mL of water. The mixture was extracted with methylene chloride,which was washed, dried and concentrated to give 1.65 g of the titlecompound.

Step 439c. (R)-1-benzyl-3-(aminomethylmorpholine

A 1.45 g sample of the compound from step 439b was dissolved in 30 mL ofethanol, 0.627 mL of hydrazine hydrate was added, and the mixture wasstirred at room temperature for 18 hours. To this solution was added13.2 mL of 1N HCl, and the mixture was heated at 70° C. for 6 hours. Thereaction was quenched by the addition of water and filtered. Thefiltrate was adjusted to pH 12 with 20% NaOH and extracted withmethylene chloride. The extract was dried, filtered and concentrated togive 667 mg of the title compound. MS 207 (M+H)⁺.

Step 439d. (R)-1-benzyl-3-(BOC-aminomethylmorpholine

The compound from step 439c (667 mg) was dissolved in 10 mL of methylenechloride, and the solution was cooled to 0° C. To this solution wasadded 0.90 1 mL of triethylamine, then 0.812 g of di-t-butyl dicarbonatein 4 mL of methylene chloride (dropwise). The reaction mixture was thenstirred at room temperature for 20 hours. The solvent was removed, andthe residue was purified by chromatography on silica gel to give 691 mgof the title compound.

Step 439e. (R)-3-(BOC-aminomethyl)morpholine

The compound from step 439d was hydrogenated in methanol over Pd/C at 4atm at room temperature for 24 hours. The mixture was filtered, and thesolvent was evaporated to give 435 mg of the title compound.

Step 439f.8-(3-(R)-(aminomethyl)morpholin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedures of Example 435b, replacing the compound of step435a with the (R)-3-(BOC-aminomethyl)morpholine from step 439e above,and carrying the product forward according to steps 435c-f, the titlecompound was prepared. MS 376 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.66 (m, 2H),1.04 (m, 2H), 2.41 (m, 1H), 2.79 (s, 3H), 2.90 (m, 1H), 3.08 (m, 1H),3.26 (m, 2H), 3.47 (m, 1H), 3.57 (m, 1H), 3.75 (m, 1H), 3.96 (m, 1H),4.04 (m, 1H), 8.01 (br s, 2H), 8.05 (s, 1H), 9.25 (d, J=9 Hz, 1H).

EXAMPLE 4408-(3-(R)-(L-alanylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 440a.8-(3-(R)-(BOC-L-alanylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

A 0.50 g sample of8-(3-(R)-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride, from Example 355 above, was dissolved in 15 mL ofDMF, and the solution was cooled to 0° C. To this solution was addeddropwise 0.484 mL of diisopropylethylamine, and the mixture was stirredfor 10 minutes. To this solution was added 0.380 g ofBOC-L-alanyl-N-hydroxy succinimide, the reaction was stirred for 20minutes, then held without stirring at 4° C. for 16 hours. This solutionwas poured into 150 mL of 1N HCl, and the precipitate was collected anddried to yield 0.755 g of the title compound.

Step 4401b.8-(3-(R)-(L-alanylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

The compound from step 440a was stirred in 12 mL of 4N HCl in dioxane atroom temperature for 70 minutes. The solvent was removed, and theresidue was triturated with ether. The solid was collected and dried,then redissolved in ethanol, which was refiltered and dried to give0.353 g of the title compound. MS 431 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.66(m, 2H), 1.03 (m, 2H), 1.37 (d, 3H, J=7.5 Hz), 1.5-2.0 (m, 5H), 2.40 (m,1H), 2.78 (s, 3H), 3.12 (m, 1H), 3.64 (m, 2H), 3.87 (m, 2H), 8.42 (d,1H, J=7.5 Hz), 9.22 (d, 1H, J=7.5 Hz), 13.86 (s, 1H). Analysiscalculated .1.5H₂ O: C, 53.49; H, 6.12; N, 11.34. Found: C, 53.25; H,6.15; N, 11.34.

EXAMPLE 4418-(3-(5-aminooctahydroindol-1-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride 441a. 5-aminooctahydroindole

A 1.0 g sample of 5-aminoindole was hydrogenated at 4 atm H₂ in 50 mL ofacetic acid over 2 g of Pt2O at room temperature for 90 hours. Thesolution was filtered, and the solvent was removed.

441b. 8-3-(5-aminooctahydroindol-1-yl),1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acidethyl ester

Following the procedure of Example 253j, substituting the5-aminooctahydroindole from step 441a for the BOC-amino-pyrrolidinethereof, the title compound was prepared.

441c.8-(3-(5-aminooctrahydroindol-1-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxquinolizine-3-carboxylic acid hydrochloride

The compound was from step 441b was treated with di-t-butyl dicarbonatein the presence of triethylamine. The resulting intermediate was treatedwith LiOH to hydrolyze the ester. The carboxylic acid compound wasdeprotected with HCl in dioxane, and the title compound was isolated(0.136 g). MS 400 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.64 (m, 2H), 1.09 (m,2H), 1.35 -3.04 (m, 11H), 2.12 (m, 1H, 2.66 (s, 3H), 4.07 (m, 2H), 4.28(m, 2H), 8.04 (s, 1H), 9.18 (d, J=10.5, 1H), 13.86 (s, 1H). Analysiscalculated for C₂₂ H₂₇ ClFN₃ O₃.2H₂ O: C, 55.99; H, 6.41; N, 8.90.Found: C, 56.08; H, 6.45; N, 8.40.

EXAMPLE 4428-(3-(2-piperidyl)piperidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 442a. 1-Boc-2-(3-pyridylpiperidine

Anabasine (0.300 g, Aldrich) was treated with di-t-butyl dicarbonate andtriethylamine in methylene chloride for 5 hours. The reaction wasquenched with water, and the mixture was extracted with methylenechloride. The extract was washed, dried and concentrated. The residuewas purified by chromatography on silica gel to give 0.36 g of the titlecompound.

Step 442b. 1-BOC-2-(3-piperidyl)piperidine

The compound of step 442a was dissolved in 25 mL of acetic acid andhydrogenated under 4 atm of H₂ over 0.36 g Pt2O for 17 hours. Themixture was filter, the solvent was removed, and the title compound wasdried under vacuum.

Step 442c.8-(3-(2-piperidyl)piperidin-1-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting the1-BOC-2-(3-piperidyl)piperidine from step 442b for theBOC-amino-pyrrolidine thereof, and carrying the product forward as insteps 253k & l, the title compound was prepared. MS 465 (M+H)⁺. ¹ H NMR(DMSO-d₆) δ: 0.72 (m, 2H), 1.07 (m, 2H), 1.52 (m, 2H), 1.79 (m, 3H),1.97 (m, 3H), 2.28 (m, 2H), 2.38 (m, 1H), 2.82 (m, 3H), 2.92 (m, 2H),3.22 (m, 2H), 3.42 (m, 2H), 3.87 (m, 2H), 8.04 (s, 1H), 9.05 (m, 1H),9.45 (m, 1H). Analysis calculated for C₂₄ H₃₂ ClFN₃ O₃ : C, 62.13; H,6.73; N, 9.06. Found: C, 61.49; H, 6.68; N, 8.91.

EXAMPLE 4438-(5-amino-decahydroisoquinolin-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 443a. 5-amino-decahydroisoquinoline

A 2 g sample of 5-aminoisoquinoline (Aldrich) was dissolved in 100 mL ofmethanol and hydrogenated at 4 atm of H₂ at room temperature for 6 daysover 0.9 g of 5% Rh/C. The mixture was filtered, and the solvent wasremoved to give the title compound.

Step 443b.8-(5-amino-decahydroisoquinolin-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting the5-amino-decahydroisoquinoline from step 442b for theBOC-amino-pyrrolidine thereof, the condensed ester was produced. Thiscompound was treated with di-t-butyl dicarbonate in the presence oftriethylamine. The resulting intermediate was treated with LiOH tohydrolyze the ester. The carboxylic acid compound was aleprotected withHCl in dioxane, and the title compound was isolated. MS 414 (M+H)⁺. ¹ HNMR (DMSO-d₆) δ: 0.67 (m, 2H), 1.03, m, 2H), 1.30-2.25 (m, 11H), 2.40(m, 1H),2.76 (s, 3H), 3.45-3.70 (m, 4H), 9.00 (m, 1H), 9.00 (m, 1H),9.20 (m, 1H). Analysis calculated for C₂₃ H₂₈ FN₃ O₃.HCl.H₂ O: C, 59.03;H, 6.46; N, 8.98. Found: C, 58.91; H, 6.77; N, 9.37.

EXAMPLE 4448-(2,7-diazabicyclo[3,3,0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 444a. 7-BOC-2-CBZ-2,7-diazabicyclo[3,3,0]octane

A 1.06 g sample of 7-BOC-2,7-diazabicyclo[3,3,0]octane (prepared as inExample 268) was dissolved in 12 mL of 1N NaOH, and the solution wascooled to 0° C. To this solution was added 1.43 mL of benzylchloroformate in 10 mL of ether over a 10 minute period, and the mixturewas stirred under N₂ for 4 hours. The mixture was extracted withmethylene chloride, and the extract was washed, dried and concentratedto give the title compound (0.40 g).

Step 444b. 2-CBZ-2,7-diazabicyclo[3,3,0]octane

The compound from step 444a was dissolved in ethyl acetate and treatedwith 4N HCl in dioxane to remove the BOC group. The solvent was removed,and the residue was dissolved in 5% NaHCO₃. The mixture was washed withethyl acetate, and the aqueous phase extracted with 1:3 i-propylalcohol:methylene chloride. The extract was washed with brine, dried andconcentrated to give 0.600 g of the title compound.

Step 444c.8-(2,7-diazabicyclo[3,3,0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting the2-CBZ-2,7-diazabicyclo[3,3,0]octane from step 444b for theBOC-amino-pyrrolidine thereof, the condensed ester was produced. Theester was hydrolyzed according to the procedure of Example 253k, thenthe CBZ group was removed by hydrogenation over Pd/C, followed byformation and isolation of the salt according to the procedure of Step253l. MS 372 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.62 (m, 2H), 1.00 (m, 2H),1.98 (m, 1H), 2.18 (m, 1H), 2.35 (m 1H), 2.69 (s, 3H), 3.12 (m, 1H),3.27 (m, 1H), 3.7 1 (m, 2H), 3.93 (m, 1H), 4.05 (m, 1H), 4.31 (m, 1H),8.00 (s, 1H), 9.17 (d, J=12 Hz, 1H). Analysis calculated for C₂₀ H₂₂ FN₃O₃.HCl.H₂ O : C, 56.40; H, 5.92; N, 9.87. Found: C, 56.57; H, 6.00; N,9.69.

EXMAPLE 4458-(3,7-diazabicyclo[3,3,0]oct-3-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 445a. 3,7-dibenzyl-2,4-dioxo-3,7-diazabicyclo[3,3,0]octane

A 1.80 g (10 mmol) sample of N-benzylmaleimide and 2.38 g (10 mmol) ofN-methoxymethyl-N-trimethylsilylmethyl-benzylamine were dissolved inmethylene chloride, and the solution was cooled to 0° C. To thissolution was added 1.00 mL (1.0 mmol) of 1.0N TFA in methylene chloridedropwise over 5 minutes. The reaction was stirred for 3 hours, thenanother 238 mg of the amine reagent was added and the mixture wasstirred at room temperature for 1 hour. The mixture was diluted with 50mL of methylene chloride and the solution was washed with 5% NaHCO₃ andbrine. The solution was dried and concentrated to give the titlecompound as a whim solid.

Step 445b. 3-benzyl-2,4-dioxo-3,7-diazabicyclo[3,3,0]octane

The compound from step 445a (3.00 g, 9.38 mmol) was dissolved in 50 mLof methanol, 500 mg of 10% Pd/C was added, and the mixture was flushedwith N₂. To this mixture was added 2.96 g (46.87 mmol) of ammoniumformate, and the reaction was stirred at 70° C. under N₂ for 1.25 hours.The mixture was diluted with methylene chloride and filtered. Thefiltrate was washed with water and concentrated. The residue wasredissolved in methylene chloride, rewashed, filtered, and the solventwas removed to give 2.37 g of the title compound.

Step 445c. 3-benzyl-3,7-diazabicyclo[3,3,0]octane

A 1.2 g (30.0 mmol) sample of LAH was suspended in ether under N₂ atroom temperature. A solution of the compound from step 445b (2.3 g, 10mmol) in methylene chloride was added dropwise over 10 minutes whilecooling the vessel in a -10° C. bath, and the mixture was stirred for 2hours. The reaction was quenched by the sequential dropwise addition of1.2 mL water, 1.2 mL 15% NaOH and 3.6 mL of water. The mixture wasfiltered, and the filtrate was concentrated to give 1.77 g of the titlecompound.

Step 445e. 3-benzyl-7-BOC-3,7-diazabicyclo[3,3,0]octane

A 1.77 g of the compound from step 445c was dissolved in a 4:1 mixtureof methanol: water, and 2.29 g of di-t-butyl dicarbonate was added. Themixture was stirred at room temperature for 1.5 hours, and the solventswere removed. The residue was dissolved in methylene chloride, and thesolution was washed with 5% NaHCCO3, brine, dried and concentrated. Theresidue was chromatographed on silica gel to give 1.68 g of the titlecompound.

Step 445e. 3-BOC-3,7-diazabicyclo[3,3,0]octane

The compound from step 445d was treated with ammonium formate and 10%Pd/C as in step 445b for 30 minutes, and the title compound was isolatedin a similar manner.

Step 445f.8-(3,7-diazabicyclo[3,3,0]oct-3-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting the3-BOC-3,7-diazabicyclo[3,3,0]octane from step 445e for theBOC-amino-pyrrolidine thereof, and carrying the product forwardaccording to steps 253k&l, the title compound (552 mg) was obtained MS372 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.6i (m, 2H), 0.99 (m, 2H), 2.33 (m,1H), 2.67 (s, 3H), 3.12 (m, 4H), 3.43 (m, 2H), 3.70 (m, 2H), 3.85 (m,2H), 7.96 (s, 1H) 9.12 (d, J=10 Hz, 1H), 13.86 (br s, 1H). Analysiscalculated for C₂₀ H₂₂ FN₃ O₃.HCl.H₂ O: C, 56.40; H, 5.92; N, 9.87.Found: C, 56.59; H, 5.80; N, 9.81.

EXAMPLE 4468-(3-carboxypyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 446a. 1-benzylpyrrolidine-3-carboxylic acid methyl ester

4.3 g of methyl acrylate and 13.09 g ofN-methoxymethyl-N-trimethylsilylmethylbenzylamine were dissolved in 100mL of methylene chloride, and the solution was cooled to 0° C. To thissolution was added 5.00 mL of 1.0N TFA in methylene chloride over a 10minute period, and the reaction was stirred at room temperature for 16hours. The mixture was washed with 5% NaHCO₃ and brine, thenconcentrated. The residue was chromatographed on silica gel to give 7.20g of the title compound.

Step 446b. 1-benzylpyrrolidine-3-carboxylamide

The compound (2.02 g) from step 446a was dissolved in 50 mL of methanol,NH3 was bubbled in until the solution was saturated, and the solutionwas stirred under balloon pressure for 4 days. Additional NH3 was added,and the mixture stirred for 2 more days. The solvent was removed to givethe title compound (1.60 g).

Step 446c. 3-carbamoyl-pyrrolidine

The compound (1.6 g) from step 446b was treated with ammonium formateand 10% Pd/C according to the procedure of step 445b for 1.75 hours, andthe title compound was isolated in a similar manner (200 mg).

Step 446d.8-(3-carboxylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253j, substituting the3-carbamoyl-pyrrolidine (1.90 g) from step 446c for theBOC-amino-pyrrolidine thereof, and carrying the product forward as instep 253k the title compound was prepared (44 mg). MS 375 (M+H)⁺. ¹ HNMR (DMSO-d₆) δ:0.60 (m, 2H), 0.98 (m, 2H), 2.20 (m, 3H), 3.16 (m, 1H),3.77 (m, 2H), 3.88 (m, 2H), 7.91 (s, 1H), 9.07 (d, J=10 Hz, 1H).Analysis calculated for C₁₉ H₁₈ FN₂ O₅.HCl.0.5H₂ O: C, 59.53; H, 5.26;N, 7.31. Found: C, 59.35; H, 5.06; N, 7.19.

EXAMPLE 4478-(3-(2,2,2-trifluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride 447a.1-benzyl-3-(2,2,2-trifluoroeacetyl)aminopyrrolidine

A 3.52 g sample of N-benzyl-3-aminopyrrolidine (prepared as in J. Med.Chem., 33:2521, 1990) was dissolved in 300 mL of methylene chloride, andthe solution was cooled to 0° C. and flushed with N₂. To this solutionwas added 4.85 mL of pyridine, then 8.45 mL of trifluoroacetic anhydride(dropwise over 10 minutes). The mixture was stirred at 0° C. for 10minutes and at room temperature for 20 minutes. The reaction mixture waswashed with 5% NaHCO₃ and brine, then filtered and concentrated to give5.76 g of the title compound.

447b. 1-benzyl-3-(2,2,2-trifluoroethyl)aminopyrrolidine

A 2.64 g sample of the compound from step 447a was added dropwise to asuspension of 1.11 g of LAH in ether stirred under N₂ at 0° C. After onehour, the reaction was stirred at room temperature for 6 hours. Thereaction was quenched by sequential addition of 1.2 mL of water, 1.2 mLof 15% NaOH and 2.4 mL of water. The mixture was filtered, and thefiltrate was concentrated to give 2.39 of the title compound.

447c. 1-benzyl-3-(N-BOC-N-(2,2,2-trifluoroethyl)aminopyrrolidine

A 2.36 g sample of the compound from step 447b was treated withdi-t-butyl dicarbonate in the THF/water, and the compound was isolatedas in previous examples (e.g., Ex. 445e). Yield 1.81 g of the titlecompound.

447d. 3-(N-BOC-N-(2,2,2-trifluoroethyl)aminopyrrolidine

A 2.80 g sample of the compound from step 447c was treated with ammoniumformate and 10% Pd/C according to the procedure of step 445b for 1.75hours, and the title compound was isolated (1.09 g).

447e.8-(3-(N-BOC-N-(2,2,2-trifluoroethyl)amino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting the3-(N-BOC-N-(2,2,2-trifluoroethyl)aminopyrrolidine (0.646 g) from step447d for the BOC-amino-pyrrolidine thereof, and carrying the productforward as in steps 253k&l the title compound was prepared (493 mg). MS428 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.60 (m, 2H), 1.93 (m, 1H), 2.10 (m,1H), 2.29 (m, 1H), 2.60 (s, 3H), 3.54 (m, 2H), 3.75 (m, 1H), 3.91 (m,2H), 7.89 (s, 1H), 9.06 (d, 1H, J=10 Hz). Analysis calculated for C₂₀H₂₀ F₄ N₃ O₃.HCl.0.25 H₂ O: C, 55.62; H, 5.02; N, 9.73. Found: C, 55.72;H, 4.83; N, 9.62.

EXAMPLE 4488-(3-(2-fluoromethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride 448a.1-benzyl-3-(N-BOC-N-(2-fluoroethyl)amino)pyrrolidine

A 3.52 g (2.00 mmol) sample of N-benzyl-3-aminopyrrolidine (prepared asin J. Med. Chem., 33:2521, 1990) and 340 mg of NaHCO₃ were dissolved in5 mL of acetonitrile. This solution was flushed with N₂ and 0.140 mL of1-bromo-2-fluoroethane (Aldrich) was added. The reaction was stirred at50° C. under N₂ for 48 hours and at 70° C. for 1.5 hours. This mixturewas cooled, and then were added 5 mL of water, 5 mL of methanol and 873mg of di-t-butyl dicarbonate. This reaction mixture was stirred for 7hours, then diluted with methylene chloride. This mixture was washedwith 5% NaHCO₃ and brine. The organic layer was dried and concentratedto give the title compound.

448b. 3-(N-BOC-N-(2-fluoroethyl)amino)pyrrolidine

A 225 mg sample of the compound from step 448a was treated with ammoniumformate and 10% Pd/C according to the procedure of step 445b for 1 hour,and the title compound was isolated (190 mg).

448b.8-(3-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting the3-(N-BOC-N-(2-fluoroethyl)amino)pyrrolidine (0.245 g) from step 448b forthe BOC-amino-pyrrolidine thereof, and carrying the product forward asin steps 253k&l the title compound was prepared (76 mg). MS 392 (M+H)⁺.¹ H NMR (DMSO-d₆) δ: 0.61 (m, 2H), 1.00 (m, 2H), 2.33 (m, 3H), 3.38 (s,3H), 3.54 (m, 1H), 3.50 (m, 1H), 3.80 (m, 1H), 4.00 (m, 4H), 4.62 (m,1H), 4.87 (m, 1H), 7.95 (s, 1H), 9.13 (d, 1H, J=10 Hz), 13.85 (br s,1H). Analysis calculated for C₂₀ H₂₃ F₂ N₃ O₃ .HCl.H₂ O: C, 53.87; H,5.88; N, 9.42. Found: C, 53.75; H, 5.61; N, 9.45.

EXAMPLE 4498-(3-((2-fluoroethyl)aminomethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedures of Example 448a-b, substituting1-benzyl-3-(BOC-amino)methylpyrrolidine (prepared according to J. Med.Chem., 1981:1320), then substituting that product for theBOC-amino-pyrrolidine forward following the procedure of Example 352j ofExample 253j, and following the procedure of 253j and carrying theproduct forward as in steps 253k&l the title compound was prepared (85mg). MS 406 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.60 (m, 2H), 1.01 (m, 2H),1.84 (m, 1H), 2.20 (m, 1H), 2.29 (m, 1H), 2.62 (s, 3H), 2.68 (m, 1H),3.16 (m, 2H), 3.78 (m, 4H), 4.80 (m, 2H), 7.91 (s, 1H), 9.08 (d, 1H,J=10 Hz). Analysis calculated for C₂₀ H₂₅ F₂ N₃ O₃.HCl.H₂ O: C, 54.84;H, 6.14; N, 9.14. Found: C, 54.23; H, 5.87; N, 8.95.

EXAMPLE 4508-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedures of Example 448, beginning with the(S)-N-benzyl-3-aminopyrrolidine, the title compound (553 mg) wasprepared. MS 392 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.62 (m, 2H), 1.00 (m,2H), 2.32 (m, 3H), 2.64 (s, 1H), 3.40 (m, 1H), 3.48 (m, 1H), 3.80 (m,1H), 4.01 (m, 4H), 4.83 (m, 2H). 7.93 (s, 1H), 9.10 (d, 1H, J=10 Hz),13.85 (br s, 1H). Analysis calculated for C₂₀ H₂₃ F₂ N₃ O₃.HCl.H₂ O: C,53.87; H, 5.88; N, 9.42. Found: C, 53.88; H, 5.75; N, 9.30.

EXAMPLE 4518-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedures of Example 448, beginning with the(R)-N-benzyl-3-aminopyrrolidine, the title compound (601 mg) wasprepared. MS 392 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.61 (m, 2H), 1.00 (m,2H), 2.32 (m, 3H), 2.64 (s, 3H), 3.40 (m, 1H), 3.48 (m, 1H), 3.80 (m,1H), 4.00 (m, 4H), 4.83 (m, 2H), 7.94 (s, 1H), 9.11 (d, 1H, J=10 Hz).Analysis calculated for C₂₀ H₂₃ F₂ N₃ O₃.HCl.H₂ O: C, 53.87; H, 5.88; N,9.42. Found: C, 53.75; H, 5.61; N, 9.45.

EXAMPLE 4528-(3a-amino-octahydroisoindol-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 452a. 2-benzyl-3a-nitro-octahydroisoindole

A 1.27 g (10.0 mmol) sample of 1-nitro-1-cyclohexene (Aldrich) and 2.38g (10.0 mmol) of N-benzyl-N-(methoxymethyl)-trimethylsilylmethylaminewere dissolved in methylene chloride, and the solution was flushed withN₂ and cooled to 0° C. To this solution was added 10 mL of methylenechloride containing 1N TFA over a 10 minute period, and the mixture wasstirred at 0° C. for 0.5 hour and at room temperature for 15 hours. Anadditional 479 mg (2 mmol) ofN-benzyl-N-(methoxymethyl)-trimethylsilylmethylamine were added, and thesolution was stirred for 5 hours. The mixture was washed with 5% NaHCO₃and brine, dried and concentrated to give 2.935 g of the title compound.

Step 452b. 2-benzyl-3a-amino-octahydroisoindole

A 520 mg sample of the compound from step 452a was dissolved in 30 andtreated with ammonium formate and 10% Pd/C according to the procedure ofstep 445b for 1 hour, and the title compound was isolated (550 mg).

Step 452c.8-(3a-amino-octahydroisoindol-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting the2-benzyl-3a-aminooctahydroisoindole (0.550 g) from step 448b for theBOC-amino-pyrrolidine thereof, then reacting the product with di-t-butyldicarbonate in methanol, and carrying the BOC-protected product forwardas in steps 253k&l the title compound was prepared (66 mg). MS 400(M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.61 (m, 2H), 1.00 (m, 2H), 2.33 (m, 3H),3.38 (s, 3H), 3.54 (m, 1H), 3.50 (m, 1H), 3.80 (m, 1H), 4.00 (m, 4H),4.62 (m, 1H), 4.87 (m, 1H), 7.95 (s, 1H), 9.13 (d, 1H, J=10 Hz), 13.85(br s, 1H). Analysis calculated for C₂₂ H₂₆ FN₃ O₃.HCl.2H₂ O: C, 55.99;H, 6.62; N, 8.90. Found: C, 55.56; H, 6.30; N, 8.95.

EXAMPLE 4538-(6-amino-2-aza-spiro[3,3]non-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride (Isomer (I))

Step 453a. 1-(2-bromoethyl)-2-oxo-cyclopentanecarboxylic acid

A 4.68 g (30 mmol) sample of 2-oxo-cyclopentanecarboxylic acid and 28.18g (150 mmol) of 1,2-dibromoethane were dissolved in 100 mL of acetone.20.73 g (150 mmol) of K2CO3 were added and the mixture was heated atreflux for 4 hours. The mixture was filtered and concentrated. Theresidue was chromatographed on silica gel to give 4.52 g of the titlecompound.

Step 453b. 2-aza-2-benzyl-spiro[3,3]nonan-1,6-dione

A 4.07 g sample of the compound from step 453a and 4.98 g of benzylaminewere dissolved in 50 mL of toluene, and the mixture was heated at refluxfor 8 hours in the presence of 14 g of 4 Å, molecular sieves. To thismixture was added 36.6 mL of 2M HCl, and the mixture was stirred at roomtemperature for 1 hour. The mixture was filtered, and the organic layerwas separated and washed with 2M HCl, dried and concentrated. Theresidue was chromatographed on silica gel to give 1.69 g of the titlecompound.

Step 453c. 2-aza-2-benzyl-spiro[3.3]nonan-6-ol

A 1.18 g (4.85 mmol) sample of the compound from step 453b was dissolvedin 15 mL of dry THF, and 14.6 mL (14.55 mmol) of LAH (1M in ether) wasadded dropwise. The mixture was heated at reflux for 2 hours, then thereaction was quenched by the sequential dropwise addition of 0.55 mLwater, 0.55 mL of 15% NaOH and 1.65 mL of water. The mixture was stirredfor 1 hour and filtered. The filtrate was dried and concentrated to give1.13 g of the title compound.

Step 453d. 2-aza-2-benzyl-spiro[3.3]nonan-6-one

A 1.13 g sample of the compound from step 453c was dissolved in 35 mL ofacetone, the solution was cooled to 0° C.m and 0.25 mL of H₂ SO4 wasadded. To this mixture was added Jones reagent dropwise, and thereaction was stirred at room temperature for 4 hours. Isopropanol wasadded, the acetone was removed under reduced pressure, and 6.5 mL of 6MNaOH was added. The mixture was filter, and the filtrate was washed withwater and brine, dried and concentrated to give 845 mg of the titlecompound.

Step 453e. 6-amino-2-aza-2-benzyl-spiro[3.3]nonane

A 845 mg sample of the compound from step 453d, 173 mg of NaBH3CN and2.84 g of ammonium acetate were dissolved in 120 mL of absolutemethanol, and the mixture was stirred at room temperature for 16 hours.The mixture was concentrated, and 200 mL of methylene chloride wereadded. The solution was filtered, and the filtrate was washed with 5%NaHCO₃, brine, dried and concentrated to give 853 mg of the titlecompound.

Step 453f. 6-(BOC-amino)-2-aza-2-benzyl-spiro[3,3]nonane

A 847 mg sample of the compound from step 453e was dissolved in 24 mL ofmethanol and 6 mL of water, and 1.61 g of di-t-butyl dicarbonate wasadded. The mixture was stirred at room temperature under N₂ for 3 hours.The mixture was concentrated, and the residue was dissolved in methylenechloride. The solution was washed with 5% NaHCO₃, dried and concentratedto give 1.40 g of the title compound.

Step 453g. 6-(BOC-amino)-2-aza-spiro[3.3]nonane

A 138 mg sample of the compound from step 453f was dissolved in 30 andtreated with ammonium formate and 10% Pd/C according to the procedure ofstep 445b for 1 hour, and the title compound was isolated (105 mg).

Step 453h.8-(6-amino-2-aza-spiro[3,3]non-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting the6-(BOC-amino)-2-aza-2-benzyl-spiro[3,3]nonane (138 mg) from step 453gfor the BOC-amino-pyrrolidine thereof, and carrying the product forwardas in steps 253k&l the title compound was prepared (57 mg).Stereoisomers were separated by HPLC. Isomer (I): MS 400 (M+H)⁺. ¹ H NMR(DMSO-d₆) δ: 0.62 (m, 2H), 1.00 (m, 2H), 1.65-2.35 (m, 11H), 2.63 (s,3H), 3.47 (m, 1H), 3.58 (m, 1H), 3.81 (m, 2H), 3.92 (m, 1H), 4.62 (m,1H), 7.93 (s, 1H), 9.09 (d, 1H, J=10 Hz). Analysis calculated for C₂₂H₂₆ FN₃ O₃.HCl.1.5H₂ O: C, 57.08; H, 6.53; N, 9.08. Found: C, 56.85; H,6.41; N, 8.84.

EXAMPLE 4548-(3-amino-3-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride 454a.1-benzyl-3-trifluoromethylpyrrolidine-3-carboxylic acid

A 2.48 g sample of 2-(trifluoromethyl)acrylic acid was dissolved in 40mL of dry methylene chloride, and a solution of 4.75 g ofN-benzyl-N-(methoxymethyl)trimethylsilylmethylamine in 20 mL of drymethylene chloride was added dropwise under N₂ at 0° C. To this mixturewas added 2 mL of trifluoroacetic acid, and the mixture was stirred for2 hours at room temperature. The product was removed by filtration,washed and dried to give the title product.

454b. 1-benzyl-3-(BOC-amino)-3-trifluoromethylpyrrolidine

A mixture of 1.42 g of the compound from step 454a, 1.71 g ofdiphenylphosphoryl azide, 12.3 g of t-butanol and 0.627 g of trimethylamine was heated at reflux under N₂ for 24 hours. The mixture wasconcentrated to dryness, and the residue was dissolved in methylenechloride. The solution was washed with satd. NaHCO₃ and water, thenconcentrated. The residue was chromatographed on silica gel to give 1.73g of the title compound.

454c. 3-(BOC-amino)-3-trifluoromethylpyrrolidine

A 413 mg sample of the compound from step 447c was treated with ammoniumformate and 10% Pd/C according to the procedure of step 445b for 2hours, and the title compound was isolated (282 mg).

454d.8-(3-amino-3-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting the3-(BOC-amino)-3-trifluoromethylpyrrolidine (227 mg) from step 453g forthe BOC-amino-pyrrolidine thereof, and carrying the product forward asin steps 253k&l the title compound was prepared (79 mg). MS 414 (M+H)⁺.¹ H NMR (DMSO-d₆) δ: 0.62 (m, 2H), 1.02 (m, 2H), 2.19 (m, 1H), 2.35 (m,2H), 2.65 (m, 3H), 3.78 (m, 2H), 4.19 (m, 2H), 7.97 (s, 1H), 9.08 (d,1H, J=10 Hz).

EXAMPLE 4558-(3-(S)-hydroxymethylazetidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid

Following the procedure of Example 253j, substituting3-(S)-hydroxymethylazetidine (540 mg) for the BOC-amino-pyrrolidinethereof, and carrying the product forward as in step 253k the titlecompound was prepared (102 mg). MS 347 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.59(m, 2H), 0.86 (m, 1H), 1.04 (m, 1H), 2.26 (m, 2H), 2.60 (s, 3H), 3.61(m, 1H), 3.77 (m, 1H), 4.23 (m, 1H), 4.58 (m, 1H), 4.91 (m, 1H), 5.06(m, 1H), 7.86 (s, 1H), 9.04 (d, 1H, J=10 Hz). Analysis calculated forC₁₈ H₁₉ FN₂ O₄.0.25H₂ O: C, 61.62; H, 5.60; N, 7.98. Found: C, 61.71; H,5.55; N, 7.81.

EXAMPLE 4568-(3-aminomethyl)-3-trifluoromethyl-pyrrolidin-1-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride 456a.1-benzyl-3-trifluoromethylpyrrolidine-3-carboxylic acid

2-(Trifluoromethyl)acrylic acid (2.48 g, 20 mmol) was dissolved in 30 mLof dry methylene chloride, a solution of 4.75 g (20 mmol) ofN-benzyl-N-(methoxymethyl)trimethylsilylmethylamine in 20 mL of drymethylene chloride was added dropwise under N₂ at 0° C. To this solutionwas added 2 mL of TFA, and the solution was stirred for 2 hours at roomtemperature. The white precipitate was collected, washed and dried togive 3.22 g of the title compound.

456b. 1-benzyl-3-trifluoromethylpyrrolidine-3-methanol

The compound from step 456a (2.32 g) was dissolved in 60 mL of dry THF,1.12 eq of LAH (1N in dry THF) was added, and the reaction was stirredunder N₂ for 3 hours. The reaction was quenched by the sequentialdropwise addition of 0.35 mL water, 0.35 mL of 15% NaOH and 1.3 mL ofwater, then the mixture was stirred for 1 hour and filtered. Thefiltrate was dried and concentrated to give 2.2 g of the title compound.

456c. 1-benzyl-3-trifluoromethyl-3-(toluenesulfonyloxymethyl)pyrrolidine

The compound from step 456b (1.61 g) was dissolved in dry pyridine, andthe solution was cooled to 0° C. To this was added 1.458 g ofp-toluenesulfonyl chloride in 4 mL of dry pyridine, and the reaction wasstirred at 0.C. for 4 days. The mixture was diluted with 300 mL ofmethylene chloride, then washed with water and brine and dried. Removalof the solvent gave 2.81 g of the title compound.

456d. 1-benzyl-3-trifluoromethyl-3-(azidomethyl)pyrrolidine

The compound (2.43 g) from step 456c was dissolved in acetonitrile, thenreacted with tetrabutylammonium azide at 80° C. for 16 hours. Themixture was diluted with methylene chloride, then washed with water andbrine and dried. Removal of the solvent gave 0.751 g of the titlecompound.

456e. 1-benzyl-3-(BOC-aminomethyl)-3-trifluoromethyl-pyrrolidine

The compound from step 456c (284 mg) and di-t-butyl dicarbonate (262 mg)were dissolved in anhydrous acetic acid and added to a suspension ofPd/C (29 mg) in 10 mL of dry acetic acid. The reaction was stirred atroom temperature under N₂ for 4 hours, then filtered The filtrate waswashed with 5% NaHCO₃ and brine, then dried and concentrated. Theresidue was purified by chromatography on silica gel to give 172 mg ofthe title compound.

456f. 3-(BOC-aminomethyl)-3-trifluoromethyl-pyrrolidine

A 330 mg sample of the compound from step 447c was treated with ammoniumformate and 10% Pd/C according to the procedure of step 445b for 2hours, and the title compound was isolated (222 mg).

456f.8-(3-aminomethyl)-3-trifluoromethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting3-(BOC-aminomethyl)-3-trifluoromethyl-pyrrolidine from step 456f (182mg) for the BOC-amino-pyrrolidine thereof, and carrying the productforward as in steps 253k&l the title compound was prepared (47 mg). MS428 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.63 (m, 2H), 1.02 (m, 2H), 2.32 (m,3H), 2.55 (m, 1H), 2.68 (s, 3H), 3.85 (m, 2H), 3.98 (m, 2H), 7.99 (s,1H), 9.16 (d, 1H, J=12 Hz). Analysis calculated for C₂₀ H₂₁ F₄ N₃ O₃.HCl.1.75H₂ O: C, 48.49; H, 5.19; N, 8.48. Found: C, 48.48; H, 4.99; N,8.49.

EXAMPLE 4578-(octahydropyrrolo[3,4-c]pyrid-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride 457a. N-benzyl-3,4-pyrrolidinedicarboxylic aciddiethyl ester

Diethyl glutaconate (7.44 g, 40 mmol) was dissolved in 60 mL of drymethylene chloride, and a solution of 9.52 g (40 mmol) ofN-benzyl-N-(methoxymethyl)trimethylsilylmethylamine in 20 mL of drymethylene chloride was added dropwise under N₂ at 0° C. To this solutionwas added 2 mL of 1N TFA in methylene chloride, and the solution wasstirred for 2 hours at room temperature. The solution was washed with 5%NaHCO₃ and brine, then dried and concentrated to give 12.48 g of thetitle compound.

457b. 2-benzyl-4.6-dioxooctahydropyrrolo[3,4-c]pyridine

A solution of 9.00 mmol of Na in liquid NH3 was prepared at -78° C. Tothis was added 15 mg of FeCl3, and the reaction mixture was warmed to-40° C. To this solution, stirred under N₂, a cooled (-40° C.) solutionof the compound (957 mg) from step 457a in THF was added over a 10minute period, and the reaction mixture was stirred at -33° C. for 3hours. Ammonium chloride (1.5 g) was added with stirring, then themixture was warmed to room temperature and the excess ammonia wasevaporated. To this was added 60 mL of water, and the mixture wasextracted with methylene chloride. The extract was washed with brine,dried and concentrated. The residue was chromatographed on silica gel togive 425 mg of the title compound.

457c. 2,5-dibenzyl-4,6-dioxooctahydropyrrolo[3,4-c]pyridine

To a mixture of 905 mg of K2CO3 and 400 mg of the compound from step457b in 5 mL of DMF was added 308 mg of benzyl bromide, and the reactionmixture was stirred at room temperature under N₂ for 6.5 hours. Themixture was diluted with ethyl acetate, which was washed With water andbrine, dried and concentrated to give 610 mg of the title compound.

457d. 5-benzyl-4,6-dioxoctahydropyrrolo[3,4-c]pyridine

A 700 mg sample of the compound from step 447c was treated with ammoniumformate and 10% Pd/C according to the procedure of step 445b for 2hours, and the title compound was isolated (540 mg).

457e. 5-benzyl-octahydropyrrolo[3,4-c]pyridine

A suspension of 266 mg of LAH in 10 mL of ether was stirred at 10° C.under N₂. To this suspension was added 540 mg of the compound from step457d dissolved in 10 mL of methylene chloride. The mixture was stirredunder N₂ for 1.5 hours. The reaction was quenched by the sequentialdropwise addition of 0.3 mL water, 0.3 mL of 15% NaOH and 0.6 mL ofwater, then the mixture was stirred for 1 hour and filtered. Thefiltrate was dried and concentrated to give 389 mg of the titlecompound.

Step 457f.8-(octahydropyrrolo[3,4-c]pyrid-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting5-benzyl-octahydropyrrolo[3,4-c]pyridine from step 457e (330 mg) for theBOC-amino-pyrrolidine thereof, and carrying the product forward as insteps 253k&l the title compound was prepared (22 mg). MS 386 (M+H)⁺. ¹ HNMR (DMSO-d₆) δ: 0.60 (m, 2H), 0.98 (m, 2H), 1.78 (m, 1H), 1.89 (m 1H),2.27 (m, 1H), 2.61 (s, 3H), 2.50-2.75 (m, 3H), 3.00 (m, 1H), 3.17 (m,2H), 3.65-4.00 (m, 4H), 7.90 (s, 1H), 9.08 (d, 1H, J=10 Hz).

EXAMPLE 4588-(3-(cyclopropylamino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride 458a. 1-benzyl-3-(cyclopropylmethyl)aminopyrrolidine

A sample (1.75 g 10 mmol) of 1-benzyl-3-pyrrolidinone was dissolved inmethylene chloride, and 1.44 g of anhydrous MgSO₄ was added. The mixturewas stirred under N₂ at 0° C., and 634 mg of cyclopropylamine was addeddropwise. The mixture was stirred at room temperature for 5 hours, then10 mL of methanol followed by 534 mg of NaBH4 in small portions wasadded. The mixture was stirred for 1 hour, then diluted with methylenechloride. The solution was washed with 5% NaHCO₃ and brine, dried andconcentrated to give 2.12 g of the title compound.

458b. 1-benzyl-3-(N-BOC-N-(cyclopropylmethyl)amino)pyrrolidine

The compound from step 458 was treated with di-t-butyl dicarbonate inacetonitrile for 2 hours, and the title compound (2.11) g was obtainedafter extraction of the compound and chromatography on silica gel.

458c. 1-benzyl-3-(N-BOC-N-(cyclopropylmethyl)amino)pyrrolidine

A 2.11 g sample of the compound from step 458b was treated with ammoniumformate and 10% Pd/C according to the procedure of step 445b for 2hours, and the title compound was isolated (1.92 mg).

458d.8-(3-(cyclopropylamino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting1-benzyl-3-(N-BOC-N-(cyclopropylmethyl)amino)pyrrolidine from step 458c(1.13 g) for the BOC-amino-pyrrolidine thereof, and carrying the productforward as in steps 253k&l the title compound was prepared. MS 386(M+H)⁺. ¹ H NMR (DMSO-d₆) δ:0.60 (m, 2H), 0.81 (m, 2H), 1.00 (m, 4H),2.34 (m, 3H), 2.64 (s, 3H), 2.83 (m, 1H), 3.30 (m, 1H), 4.06 (m, 4H),7.93 (s, 1H), 9.11 (d, 1H, J=10 Hz).

EXAMPLE 4598-(6-amino-2-aza-spiro-[3,3]non-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride (Isomer (II))

The second stereoisomer (Isomer II) from Example 453 was also obtainedby HPLC. Isomer (II): MS 400 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ:0.62 (m, 2H),1.00 (m, 2H), 1.60-1.95 (m, 6H), 2.30 (m, 2H), 2.60 (s, 3H), 3.47 (m,1H), 3.52 (m, 1H), 3.85 (m, 4H), 7.90 (s, 1H), 9.09 (d, 1H, J=10 Hz).Analysis calculated for C₂₂ H₂₆ FN₃ O₃.HCl.H₂ O: C, 58.21; H, 6.44; N,9.26. Found: C, 58.00; H, 6.29; N, 8.86.

EXAMPLE 4608-(2,7-diazabicyclo[3,3,0]oct-7-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-3-carboxylicacid hydrochloride Isomer A

7-BOC-2-CBZ-2,7-diazabicyclo[3,3,0]octane was prepared according to theprocedure of Example 444. This compound was separated by HPLC into twostereoisomers. Isomer A was carried forward according to the proceduresof steps 444b and 444c to give the title compound (194 mg). MS 372(M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.62 (m, 2H), 1.00 (m, 2H), 1.98 (m, 1H),2.18 (m, 1H), 2.35 (m, 1H), 2.69 (s, 3H), 3.12 (m, 1H), 3.27 (m, 1H),3.71 (m, 2H), 3.93 (m, 1H), 4.05 (m, 1H), 4.31 (m, 1H), 8.00 (s, 1H),9.17 (d, J=11 Hz, 1H). Analysis calculated for C₂₀ H₂₂ FN₃ O₃.HCl.1.75H₂ O : C, 55.66; H, 6.08; N, 9.56. Found: C, 54.68; H, 5.73; N, 9.54.

EXAMPLE 4618-(2,7-diazabicyclo[3,3,0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride Isomer B

7-BOC-2-CBZ-2,7-diazabicyclo[3,3,0]octane was prepared according to theprocedure of Example 444. This compound was separated by HPLC into twostereoisomers. Isomer B was carried forward according to the proceduresof steps 444b and 444c to give the title compound (263 mg). MS 372(M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.62 (m, 2H), 1.00 (m, 2H), 1.98 (m, 1H),2.18 (m, 1H), 2.36 (m, 1H), 2.69 (s, 3H), 3.13 (m, 1H), 3.28 (m, 1H),3.71 (m, 2H), 3.91 (m, 1H), 4.04 (m, 1H), 4.31 (m, 1H), 8.00 (s, 1H),9.17 (d, J=11 Hz, 1H). Analysis calculated for C₂₀ H₂₂ FN₃ O₃. HCl.1.5H₂ O: C, 55.24; H, 6.03; N, 9.66. Found: C, 55.37; H, 5.79; N, 9.59.

EXAMPLE 4628-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-3quinolizine-3-carboxylicacid hydrochloride

Step 462a. 1-(1-(R)-phenylethyl)pyrrolidine-3-(R)-methanol

A 2.61 g (10 mmol) sample of5-oxo-1-(1-(R)-phenylethyl-3-(R)-pyrrolidine carboxylic acid ethyl ester(prepared as described by D. R. Johnson et at., J. Heterocyclic Chem.,29:1481 (1992)) and 0.95 g of LAH were suspended in 20 mL of dry THF,and the reaction mixture was stirred at room temperature for 16 hours.The reaction was quenched by the sequential addition of water, 15% NaOHand water. The mixture was extracted with ether, which was washed, driedand concentrated to give the title compound (1.8 g) as an oil. MS 206(M+H)⁺. ¹ H NMR (CDCl₃) δ: 1.4 (d, 3H), 1.6-1.7 and 1.9-2.01 (m, 3H),2.2-2.5 (m, 3H), 2.55-2.65 (tt, 1H), 3.13-3.2 (1, 1H), 3.5-3.57 (dd,1H), 3.7-3.76 (dd, 1H), 7.2-7.32 (m, 5H).

Step 462b. 3-(R)-pyrrolidinemethanol

A sample of the compound from step 462a was dissolved in methanol, 10%Pd/C was added, and the mixture was hydrogenated at 4 atm H₂ for 16hours at room temperature. The solution was filtered, and the solventwas removed. The residue was taken directly to the next step.

462c.8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting3-(R)-pyrrolidinemethanol from step 462b for the BOC-amino-pyrrolidinethereof, and carrying the product forward as in steps 253k&l the titlecompound was prepared. MS 361 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.6-0.75 (m,2H), 0.9-1.05 (m, 2H), 1.85-1.95 (m, 1H), 2.1-2.2 (m, 2H), 2.45 (m, 1H),2.6 (s, 3H), 3.7-4.03 (m, 6H), 8.15 (s, 1H), 9.02 (d, 1H, J=12 Hz).

EXAMPLE 4638-(3-(S)-(hydroxymethylpyrrolidin-1-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 463a. 1-(1-(R)-phenylethyl)pyrrolidine-3-(S)-methanol

A 2.61 g (10 mmol) sample of5-oxo-1-(1-(R)-phenylethyl-3-(S)-pyrrolidine carboxylic acid ethyl ester(prepared as described by D. R. Johnson et al., J. Heterocyclic Chem.,29:1481 (1992)) and 0.95 g of LAH were suspended in 20 mL of dry THF,and the reaction mixture was stirred at room temperature for 16 hours.The reaction was quenched by the sequential addition of water, 15% NaOHand water. The mixture was extracted with ether, which was washed, driedand concentrated to give the title compound as an oil. MS 206 (M+H)⁺. ¹H NMR (CDCl₃) δ: 1.39 (d, 3H), 1.7-1.8 and 1.94-2.07 (m, 3H), 2.2-2.46(m, 3H), 2.97-3.05 (tt, 1H), 3.12-3.2 (1, 1H), 3.45-3.53 (dd, 1H),3.6-3.65 (dd, 1H), 7.2-7.35 (m, 5H).

Step 462b. 3-(S)-pyrrolidinemethanol

A sample of the compound from step 462a was dissolved in methanol, 10%Pd/C was added, and the mixture was hydrogenated at 4 atm H₂ for 16hours at room temperature. The solution was filtered, and the solventwas removed. The residue was taken directly to the next step.

463c.8-(3-(S)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting3-(R)-pyrrolidinemethanol from step 463b for the BOC-amino-pyrrolidinethereof, and carrying the product forward as in steps 253k&l the titlecompound was prepared. MS 361 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.6-0.75 (m,2H), 0.9-1.05 (m, 2H), 1.85-1.9 (m, 1H), 2.15-2.2 (m, 2H), 2.55-2.6 (s,1H), 2.65 (s, 3H), 3.65-3.85 (m, 6H), 8.19 (s, 1H), 9.08 (d, 2H).

EXAMPLE 4648-(2-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting2-(R)-pyrrolidinemethanol (Aldrich) for the BOC-amino-pyrrolidinethereof, and carrying the product forward as in steps 253k&l the titlecompound was prepared. ¹ H NMR (DMSO-d₆) δ:0.5-1.1 (m, 2H), 1.9-2.2 (m,5H), 2.68 (s, 3H), 3.22 (s, 1H), 3.62 (m, 1H), 4.0 (m, 2H), 4.55 (m,1H), 7.95 (s, 1H), 9.0 (d, 2H).

EXAMPLE 4658-(2-(S)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting2-(S)-pyrrolidinemethanol (Aldrich) for the BOC-amino-pyrrolidinethereof, and carrying the product forward as in steps 253k&l the titlecompound was prepared. ¹ H NMR (DMSO-d₆) δ: 0.5-1.2 (m, 4H), 1.8-2.0 (m,5H), 2.67 (s, 3H), 3.22 (m, 1H), 3.65 (m, 1H), 4.0 (m, 2H), 4.57 (m,1H), 7.9 (s, 1H), 9.0 (d, 2H).

EXAMPLE 4668-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting2-(R)-BOC-aminomethyl)pyrrolidine (prepared as described in JP87-236335)for the BOC-aminopyrrolidine thereof, and carrying the product forwardas in steps 253k&l the title compound was prepared. MS 360 (M+H)⁺. ¹ HNMR (DMSO-d₆) δ: 0.61 (m, 2H), 0.92 (m, 1H), 1.10 (m, 1H), 1.87 (m, 2H),2.06 (m, 1H), 2.64 (s, 3H), 2.84 (m, 1H), 2.94 (m, 1H), 3.92 (m, 1H),4.53 (m, 1H), 8.00 (s, 1H), 9.18 (d, 1H). HRMS (M+H)⁺ : calculated forC₁₉ H₂₃ FN₃ O₃ :360.1723; found:360.1713.

EXAMPLE 4678-(2-(S)-aminomethyl-pyrrolidin-1-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting2-(S)-(BOC-aminomethyl)pyrrolidine (prepared as described inJP87-236335) for the BOC-aminopyrrolidine thereof, and carrying theproduct forward as in steps 253k&l the title compound was prepared. MS:360 (M+H)⁺. ¹ H NMR (DMSO-d₆) δ: 0.60 (m, 2H), 0.92 (m, 1H), 1.09 (m,1H), 1.87 (m, 2H), 2.06 (m, 1H), 2.26 (m, 1H), 2.35 (m, 1H), 2.64 (s,3H), 2.84 (m, 1H), 2.97 (m, 1H), 3.91 (m, 1H), 4.54 (m, 1H), 8.01 (s,1H), 9.16 (d, 1H), 13.84 (b, 1H). HRMS (M+H)⁺ : calculated for C₁₉ H₂₃FN₃ O₃ : 360.1723; found:360.1730.

EXAMPLE 4688-(3-(R)-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride 468a.4-(R)-(1-(BOC-amino)cyclopropyl)pyrrolidin-2-thione and 4-(S)-(1-(BOC-amino)cyclopropyl)pyrrolidin-2-thione

A sample of 4-(1-(BOC-amino)cyclopropyl)-pyrrolidin-2-one (4.3 g,17.92mmol, prepared as described by Hayakawa et at., U.S. Pat. No. 5,098,912,issued Mar. 24, 1992) and 3.987 g of Lawesson's Reagent were suspendedin 41 mL of THF, and the reaction mixture was stirred under N₂ for 3hours at room temperature. The solvent was removed, and the residue wasdissolved in 1% methanol in methylene chloride and purified bychromatography on silica gel to give 3.773 g of the title compound. MS:257 (M+H)⁺. This compound was subjected to chiral HPLC to separate the Rand S isomers.

468b. 3-(R)-(1-(BOC-amino)cyclopropylpyrrolidine

A sample of the (R)-isomer (203 mg) from step 468a and 1.51 g ofNiCL2.6H₂ O were dissolved in 10 mL of 1:1 methanol:THF, and thesolution was cooled in an ice bath. To this was added 720 mg of NaBH4 inportions, and the reaction mixture was stirred at room temperature for 2hours. The solvent was removed, and the residue was purified bychromatography on silica gel to give the title compound.

468c.8-(3-(R)-1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting3-(R)-(1-(BOC-amino)cyclopropyl)pyrrolidine from step 468b for theBOC-amino-pyrrolidine thereof, and carrying the product forward as insteps 253k&l the title compound was prepared. The spectroscopic datawere similar to the racemic mixture of Example 311 above.

EXAMPLE 4698-(3-(S)-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride 469a. 3-(S)-(1-(BOC-amino)cyclopropyl)pyrrolidine

A sample of the (S)-isomer (194 mg) from Example 468a above and 1.46 gof NiCL2.6H₂ O were dissolved in 10 mL of 1:1 methanol:THF, and thesolution was cooled in an ice bath. To this was added 690 mg of NaBH4 inportions, and the reaction mixture was stirred at room temperature for 2hours. The solvent was removed, and the residue was purified bychromatography on silica gel to give the title compound.

469b.8-(3-(S)-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting3-(S)-(1-(BOC-amino)cyclopropyl)pyrrolidine from step 468b for theBOC-amino-pyrrolidine thereof, and carrying the product forward as insteps 253k&l the title compound was prepared. The spectroscopic datawere similar to the racemic mixture of Example 311 above.

EXAMPLE 4708-(3-(1-amino-1-cyclopropyl-methyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride 470a. 1-cyclopropyl-prop-2-ene-1-one

A sample (5 g, 59 mmol) of 1-cyclopropyl methyl ketone (Aldrich) wasdissolved in 59 mL of THF, and the solution was heated at reflux underN₂, then cooled. Another solution 7.97 g of formalin and 19.57 g ofN-methylpyridinium trifluoroacetate was prepared. Half of the secondsolution was added to the cooled first solution, and this mixture wasthen heated at reflux for half an hour. The reaction mixture was thencooled, the second half of the second solution was added, and thereaction mixture heated at reflux for 7 hours. The mixture was cooled,and ether (100 mL) was added slowly with stirring, and a gummyprecipitate was obtained. The gum was triturated with ethers. The ethersolutions were combined and extracted with aqueous NaHCO₃. The ethersolution was dried, filtered and concentrated. The residue wastriturated with ether, and the ether solution was again dried, filteredand concentrated to give 4.60 g of the title compound.

470b. (1-benzyl-pyrroldin-3-yl)-cyclopropyl-methanone

A 2 g sample of the compound from step 470a and 4.94 g ofN-benzyl-N-(methoxymethyl)-trimethylsilylmethylamine were dissolved inmethylene chloride, and the solution was cooled in an ice bath. To thissolution was added 2.1 mL of TFA (1N in methylene chloride), and thereaction mixture was stirred at room temperature for 2 hours. Themixture was diluted with methylene chloride, and the solution was washedwith NaHCO₃, water and brine, then concentrated. The residue waspurified by chromatography on silica gel to give 2.037 g of the titlecompound.

470c. 1-(1-benzyl-pyrroldin-3-yl)-1-cyclopropyl-methylamine

A 1 g sample of the compound from step 470b, 3.37 g of ammonium acetateand 274 mg of NaBH₃ CN were dissolved in 15 mL of methanol, 1.2 g of 4 Åmolecular sieves were added, and the mixture was stirred at roomtemperature under N₂ for 16 hours. The mixture was filtered, the sieveswashed with methanol, the wash and filtrate combined, and concentrated.The residue was dissolved in 100 mL of methylene chloride, and 30 mL of15% NaOH was added. The organic phase and a second wash of the aqueousphase were combined and washed with water and brine, then dried overMgSO₄. The solvent was removed, and the residue was chromatographed onsilica gel to give 460 mg of the title compound.

470d. N-BOC-1-(1-benzyl-pyrroldin-3-yl)-1-cyclopropyl-methylamine

The compound from step 470c was treated with di-t-butyl dicarbonate inmethylene chloride and triethylamine for 2 hours, and the title compound(640 mg) was obtained after chromatography on silica gel.

470e. 3-(1-(BOC-amino)-1-cyclopropyl-methyl)pyrrolidine

A sample (548 mg) of the compound from step 470d was dissolved inmethanol, 140 mg of 10% Pd/C was added, and the mixture was hydrogenatedat 4 arm H₂ for 42 hours at room temperature. The solution was filtered,and the solvent was removed to give 140 mg of the title compound.

470f.8-(3-(1-amino-1-cyclopropyl-methyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting3-(1-(BOC-amino)-1-cyclopropyl-methyl)pyrrolidine from step 470e for theBOC-amino-pyrrolidine thereof, and carrying the product forward as insteps 253k&l the title compound was prepared. ¹ H NMR (DMSO-d₆) δ: 0.46(m, 1H), 0.62 (m, 4H), 0.92 (m, 1H), 1.03 (m, 2H), 1.82 (m, 1H), 2.27(m, 3H), 2.61 (s, 3H), 3.74 (m, 2H), 3.89 (m, 2H), 7.90 (s, 1H), 9.07(d, 1H), 13.83 (br s, 1H). HRMS (M+H)⁺ : calculated for C₂₂ H₂₇ FN₃ O₃ :400.2036; found: 400.2030.

EXAMPLE 471 8-(3-(R)-pyrrolidin-2-(S)-yl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acidhydrochloride 471a. 3-(R)-(1-BOC-2-(S)-pyrrolidinyl)-4-nitrobutanol

A 7.5 g sample of ethyl3-(R)-(1-BOC-2-(S)-pyrrolidinyl)-4-nitrobutanoate (prepared according tothe procedure of Hayakawa et al., U.S. Pat. No. 5,098,912, issued Mar.24, 1992) was dissolved in 35 mL of ether and treated with 0.76 g ofLAH. After careful quenching of the excess reagents, the title compoundwas extracted and purified by chromatography (4.5 g).

471a. 3-(R)-(1-BOC-2-(S)-pyrrolidinyl)-4-nitrobutanyl methylsulfonylether

A 3.5 g sample of the alcohol from step 471a above was dissolved in 25mL of methylene chloride and treated with methanesulfonyl chloride anTEA at 0° C. for 2 hours. The reaction mixture was washed with NaHCO₃solution and water, and the solvent was removed. The residue waschromatographed on silica gel to give 3 g of the title compound.

471c. 3-(R)-(1-BOC-pyrrolidin-2-(S)-yl)pyrrolidine

The ether compound from step 471a was treated by hydrogenation at 4 atmH₂ over Pd/C in methanol to give the tile compound.

471d.8-(3-(R)-(pyrrolidin-2-(S)-yl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting3-(R)-(1-BOC-pyrrolidin-2-(S)-yl)pyrrolidine from step 471c for theBOC-amino-pyrrolidine thereof, and carrying the product forward as insteps 253k&l the title compound was prepared. MS 400 (M+H)⁺. ¹ H NMR(DMSO-d₆) δ:0.58-0.62 (m, 2H), 0.9-1.1 (m, 2H), 1.68-2.8 (m, 8H), 2.5(s, 3H), 3.1-3.8 (m, 7H), 7.9 (s, 1H), 9.08 (dd, 2H).

EXAMPLE 4728-(3-(aminomethyl)azetidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride 472a. 3-(BOC-aminomethyl)-1-diphenylmethyl-azetidine

A sample (0.6 g) of 3-aminomethyl-1-diphenylmethyl-azetidine (preparedaccording to Anderson and Lok, J. Org. Chem., 37:3393-5 (1972)) wastreated with di-t-butyl dicarbonate in methylene chloride andtriethylamine for 2 hours, and the title compound (450 mg) was obtainedafter chromatography on silica gel.

472b. 3-(BOC-aminomethyl)-azetidine

A sample of the compound from step 473a was treated with 4 atm of H₂ inthe presence of Pd/C in methanol at room temperature. The mixture wasfiltered, and the solvent was removed to give the title compound.

472c.8-(3-(aminomethyl)azetidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253j, substituting3-(BOC-aminomethyl)-azetidine from step 472b for theBOC-amino-pyrrolidine thereof, and carrying the product forward as insteps 253k&l the title compound was prepared. MS 346 (M+H)⁺. ¹ H NMR(DMSO-d₆) δ: 0.61 (m, 2H), 0.98 (m, 2H), 2.16 (m, 1H), 2.60 (s, 3H),3.01 (m, 1H), 3.76 (m, 1H), 4.41 (m, 2H), 4.69 (m, 2H), 7.88 (s, 1H),9.10 (d, 1H).

EXAMPLE 4736-amino-8-(3-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 473a-a: 4-t-Butoxy-6-dibenzylamino-2,5-difluoro-3-methylpyridine

4-t-Butoxy-2,5,6-trifluoro-3-methylpyridine from Step 253c above isreacted with dibenzylamine in ethanol at reflux temperature. Solvent isremoved, and the residue is dissolved in methylene chloride and washedwith water. The product is purified by column chromatography.

Step 473b:6-dibenzylamino-8-(3-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 253e, replacing4-t-butoxy-2,5-difluoro-3-methylpyridine with4-t-butoxy-6-dibenzylamino-2,5-difluoro-3-methylpyridine from Step 473aabove, and carrying the product forward as in Example 253 steps e-l, thetitle compound is prepared.

Step 473c:6-amino-8-(3-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

A sample from Step 473d above is heated with ammonium formate in thepresence of 10% Pd-C in ethanol. After the completion of the reaction,the mixture is filtered and the filtrate is concentrated and treatedwith HCl in ether to give the title compound.

EXAMPLE 4746-amino-8-(7-amino-5-azaspiro[2,4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedures of Example 473, replacing3-BOC-aminopyrrolidine with 7-BOC-amino-5-azaspiro[2,4]heptane (preparedaccording to the procedures as described in J. Med. Chem. 1994, 37,3344), and carrying the product forward the title compound is prepared.

EXAMPLE 4756-amino-8-(2,8-diaza-8-bicyclo[4,3,0]nonyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedures of Example 473, replacing3-BOC-aminopyrrolidine with 2,8-diazabicyclo[4,3,0]nonane (preparedaccording to U.S. Pat. No. 5,059,597), and carrying the product forwardthe title compound is prepared.

EXAMPLE 4766-amino-8-(3,5-cis-dimethylpiperazin-1-yl)-1-cyclopropyl-7,9-difluoro-4H-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Following the procedure of Example 473a, replacing4-t-butoxy-2,5,6-trifluoro-3-methylpyridine with4-t-butoxy-2,3,5,6-tertafluoropyridine from Example 274b above, andcarrying the product forward as in Example 473b-c, replacing3-BOC-aminopyrrolidine with 3,5-cis-dimethylpiperazine and carrying theproduct forward the title compound is prepared.

EXAMPLE 4778-(1-amino-1-cyclopropyl)-1-cyclopropyl-7-fluoro-9-methyl-4H-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 477a:1-cyclopropyl-8-(diphenylmethoxycarbonylmethyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester

To a suspension of NaH in DMF with ice bath cooling is added di-t-butylmalonate. After the addition,8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester from Example 253i above is added. The reaction is thenheated to 50° to 60° C., and the mixture is poured into water andacidified. The product is extracted into methylene chloride and driedover MgSO₄. The residue, after removal of the solvent, is dissolved inmethylene chloride and trifluoroacetic acid at room temperature. Thesolvent is removed under vacuum, and the product is treated withdiphenyldiazomethane in methylene chloride and methanol. When thereaction is finished, the solvents are removed under vacuum, and theproduct is purified by column chromatography to give the title compound.

Step 477b:1-cyclopropyl-8-(1-diphenylmethoxycarbony-1-vinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester

The product from Step 477a is heated with 35% formaldehyde in DMF in thepresence sodium bicarbonate. When the reaction is complete, the productis extracted into methylene chloride, washed with water and dried overMgSO₄. The solvent is removed, and the residue is dissolved methylenechloride. Triethylamine is added, followed by methanesulfonyl chloridewith ice bath cooling. After the addition, the reaction is stirred atroom temperature, then poured into water and acidified. The mixture isextracted with ethylene chloride, and the solvent is removed to give thecrude product, which is purified by column chromatography.

Step 477c:1-cyclopropyl-8-(1-diphenylmethoxycarbony-1-cyclopropyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester

Trimethylsulfonium iodide is added to a stirred solution of NaH in DMSOat 0° C. and the resulting solution is stirred at room temperature. Theproduct from Step 477b above is added and mixture is stirred at 50° C.The mixture is quenched with water, and the product is extracted to givethe title compound.

Step 477d:1-cyclopropyl-8-(1-hydroxycarbonyl-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester

The product from Step 477d is dissolved in the mixture of anisol andtrifluoroacedic acid and is stirred at room temperature. The solventsare removed and residue is purified by a column chromatography to givethe title compound.

Step 477e:1-cyclopropyl-8-(1-Bocamino-1-cyclopropyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester

A sample of the product from Step 477d is heated with diphenylphosphorylazide, t-butanol, triethylamine and dioxane. The solvents is removedunder vacuum. The residue is dissolved in methylene chloride, washedwith water and dried over MgSO₄ and concentrated under vacuum. The titlecompound is purified by chromatography on silica gel.

Step 477f:1-cyclopropyl-8-(1-amino-1-cyclopropyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid hydrochloride

The product from Step 477e is treated by procedures as described inExample 253 k-l to give the title compound.

EXAMPLE 4783(R)-10-(1-amino-1-cyclopropyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2,3,4-ij]quinolizine-5-carboxylicacid hydrochloride

Follow the procedures as described in Example 477, replacing8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester with3(R)-10-chloro-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2,3,4-ij]quinolizine-5-carboxylicacid ethyl ester from Example 281e to give the title compound.

EXAMPLE 4798-(1-amino-1-cyclopropyl)-1-cyclopropyl-7-fluoro-9-methoxy-4H-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Follow the procedures as described in Example 477, replacing8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester with8-chloro-1-cyclopropyl-7-fluoro-9-methoxy-4H-4-oxo-quinolizine-3-carboxylicacid ethyl ester from Example 275 to give the title compound.

EXAMPLE 4808-(1-aminomethyl-1-cyclopropyl)-1-cyclopropyl-7-fluoro-9-methyl-4H-4-oxo-quinolizine-3-carboxylicacid hydrochloride

Step 480a:8-(1-cyano-1-cyclopropyl)-1-cyclopropyl-7-fluoro-9-methyl-4H-4-oxo-quinolizine-3-carboxylicacid ethyl ester

The product from Example 477d is treated with oxalyl chloride inmethylene chloride followed by quenching with aqueous ammonia. Aqueouswork up gives the amide, which is treated with POCl₃ at room temperatureto give the title compound.

Step 480b:8-(1-Bocaminomethyl-1-cyclopropyl)-1-cyclopropyl-7-fluoro-9-methyl-4H-4-oxo-quinolizine-3-carboxylicacid ethyl ester

The product from Step 480a is treated with Raney Ni in ethanol underhydrogen. The residue after removal of the solvent is reacted withd-t-butyl dicarbonate in the mixture of methanol and water. Reaction isextracted into methylene chloride, washed with water and dried overMgSO₄ and concentrated trader vacuum. The title compound is purified bychromatography on silica gel.

Step 480c:8-(1-aminomethyl-1-cyclopropyl)-1-cyclopropyl-7-fluoro-9-methyl-4H-4-oxo-quinolizine-3-carboxylicacid hydrochloride

The product from Step 480b is treated by procedures as described inExample 253 k-l to give the title compound.

EXAMPLES 481-565

Following the procedures of Steps 253j, 253k and 253l above, replacingthe 3-BOC-aminopyrrolidine of Step 253j with the appropriate unprotectedor BOC-protected reagent, the compounds of Examples 481-565 are preparedas shown in Table 13A, below. In those cases wherein specific chiralisomers are indicated, the examples are to be understood as alsorepresenting the opposite stereoisomers and diasteromers thereof.

                  TABLE 13A                                                       ______________________________________                                         ##STR262##                                                                   Example #                                                                             R.sup.2                                                               ______________________________________                                        481                                                                                    ##STR263##                                                           482                                                                                    ##STR264##                                                           482                                                                                    ##STR265##                                                           484                                                                                    ##STR266##                                                           485                                                                                    ##STR267##                                                           486                                                                                    ##STR268##                                                           487                                                                                    ##STR269##                                                           488                                                                                    ##STR270##                                                           489                                                                                    ##STR271##                                                           490                                                                                    ##STR272##                                                           491                                                                                    ##STR273##                                                           492                                                                                    ##STR274##                                                           493                                                                                    ##STR275##                                                           494                                                                                    ##STR276##                                                           495                                                                                    ##STR277##                                                           496                                                                                    ##STR278##                                                           497                                                                                    ##STR279##                                                           498                                                                                    ##STR280##                                                           499                                                                                    ##STR281##                                                           500                                                                                    ##STR282##                                                           501                                                                                    ##STR283##                                                           502                                                                                    ##STR284##                                                           503                                                                                    ##STR285##                                                           504                                                                                    ##STR286##                                                           505                                                                                    ##STR287##                                                           506                                                                                    ##STR288##                                                           507                                                                                    ##STR289##                                                           508                                                                                    ##STR290##                                                           509                                                                                    ##STR291##                                                           510                                                                                    ##STR292##                                                           511                                                                                    ##STR293##                                                           512                                                                                    ##STR294##                                                           513                                                                                    ##STR295##                                                           514                                                                                    ##STR296##                                                           515                                                                                    ##STR297##                                                           516                                                                                    ##STR298##                                                           517                                                                                    ##STR299##                                                           518                                                                                    ##STR300##                                                           519                                                                                    ##STR301##                                                           520                                                                                    ##STR302##                                                           521                                                                                    ##STR303##                                                           522                                                                                    ##STR304##                                                           523                                                                                    ##STR305##                                                           524                                                                                    ##STR306##                                                           525                                                                                    ##STR307##                                                           526                                                                                    ##STR308##                                                           527                                                                                    ##STR309##                                                           528                                                                                    ##STR310##                                                           529                                                                                    ##STR311##                                                           530                                                                                    ##STR312##                                                           531                                                                                    ##STR313##                                                           532                                                                                    ##STR314##                                                           533                                                                                    ##STR315##                                                           534                                                                                    ##STR316##                                                           535                                                                                    ##STR317##                                                           536                                                                                    ##STR318##                                                           537                                                                                    ##STR319##                                                           538                                                                                    ##STR320##                                                           539                                                                                    ##STR321##                                                           540                                                                                    ##STR322##                                                           541                                                                                    ##STR323##                                                           542                                                                                    ##STR324##                                                           543                                                                                    ##STR325##                                                           544                                                                                    ##STR326##                                                           545                                                                                    ##STR327##                                                           546                                                                                    ##STR328##                                                           547                                                                                    ##STR329##                                                           548                                                                                    ##STR330##                                                           549                                                                                    ##STR331##                                                           550                                                                                    ##STR332##                                                           551                                                                                    ##STR333##                                                           552                                                                                    ##STR334##                                                           553                                                                                    ##STR335##                                                           554                                                                                    ##STR336##                                                           555                                                                                    ##STR337##                                                           556                                                                                    ##STR338##                                                           557                                                                                    ##STR339##                                                           558                                                                                    ##STR340##                                                           559                                                                                    ##STR341##                                                           560                                                                                    ##STR342##                                                           561                                                                                    ##STR343##                                                           562                                                                                    ##STR344##                                                           563                                                                                    ##STR345##                                                           564                                                                                    ##STR346##                                                           565                                                                                    ##STR347##                                                           ______________________________________                                    

EXAMPLE 566 In Vitro Assay Of Antibacterial Activity

The in vitro antibacterial activity of the compounds of the presentinvention was demonstrated as follows: Minimum inhibitory concentrations(MICs) were determined by the agar dilution method, in which twelvepetri dishes were prepared, each containing successive aqueous 2-folddilutions of the test compounds mixed with 10 mL of sterilized BrainHeart Infusion (BHI) agar. Each plate was inoculated with 1:100 (or 1:10for slow-growing strains, primarily Micrococcus and Streptococcus)dilutions of up to 32 different microorganisms, using a Steersreplicatoro block calibrated to deliver approximately 10⁴ colony formingunits (CFUs). The inoculated plates were incubated at from about 35° C.to about 37° C. for approximately 20-24 hours. In addition, a controlplate using BHI agar containing no test compound was prepared andincubated at the beginning and at the end of each test. The quinoloneantibacterial ciprofloxacin was used as a control ("Cntl").

After incubation, each petri dish was observed for the presence orabsence of microorganism growth. The MIC was defined as the lowestconcentration of test compound yielding no growth (a slight haze orsparsely isolated colonies at the inoculum spot) as compared to thegrowth control containing no test compound.

The results of the above tests, shown in Tables 14, 15 and 16 below,demonstrate that the compounds of the present invention are surprisinglyeffective in combating bacterial growth. Moreover, the 9-methylquinolizinone compounds of the invention (in which A of formula (I) is═CR⁶ - and R⁶ is methyl) are shown to have excellent activity evenagainst the ciprofloxacinresistant pathogen Staphylococcus aureus 1775,demonstrating the potential usefulness of these compounds in treatinginfections not susceptible to this widely-used agent.

                                      TABLE 14                                    __________________________________________________________________________    In Vitro Antibacterial Activity (MIC Values in μg/ml)                                        Example Number                                              Organism          Cntl 1   2  62  64   65   157                               __________________________________________________________________________    Staphylococcus aureus ATCC 6538P                                                                0.2  0.39                                                                              0.39                                                                             3.1 25   12.5 0.2                               Staphylococcus aureus A5177                                                                     0.39 0.78                                                                              0.78                                                                             12.5                                                                              50   25   0.39                              Staphylococcus aureus A-5278                                                                    0.39 --  0.78                                                                             --  --   --   0.39                              Staphylococcus aureus 642A                                                                      0.39 0.78                                                                              0.78                                                                             6.2 --   --   0.39                              Staphylococcus aureus NCTC 10649                                                                0.39 0.39                                                                              0.39                                                                             6.2 --   --   0.2                               Staphylococcus aureus CMX 553                                                                   0.78 0.78                                                                              0.78                                                                             12.5                                                                              50   50   0.39                              Staphylococcus aureus 1775                                                                      >100 --  25 --  --   --   25                                Staphylococcus epidermidis 3519                                                                 0.39 0.78                                                                              0.78                                                                             12.5                                                                              50   25   0.39                              Micrococcus luteus ATCC 9341                                                                    1.56 50  50 25  25   25   3.1                               Micrococcus luteus ATCC 4698                                                                    0.78 25  25 12.5                                                                              25   25   1.56                              Enterococcus faecium ATCC 8043                                                                  0.39 25  25 50  100  50   1.56                              Streptococcus bovis A5169                                                                       1.56 25  25 25  25   100  3.1                               Streptococcus agalactaciae CMX 508                                                              0.39 12.5                                                                              12.5                                                                             25  50   100  1.56                              Streptococcus pyrogenes EES61                                                                   0.39 6.2 6.2                                                                              25  50   100  1.56                              Streptococcus pyrogenes CONST                                                                   0.78 6.2 6.2                                                                              25  50   50   1.56                              Streptococcus pyrogenes 2548 INDUC                                                              0.39 3.1 3.1                                                                              25  50   50   0.39                              Escherichia coli JUHL                                                                           0.01 0.39                                                                              0.39                                                                             3.1 6.2  12.5 0.02                              Escherichia coli SS                                                                             .005 <.05                                                                              0.05                                                                             0.39                                                                              1.56 1.56 0.01                              Escherichia coli DC-2                                                                           0.2  12.5                                                                              12.5                                                                             25  100  >100 0.39                              Escherichia coli H560                                                                           0.01 --  0.39                                                                             3.1 12.5 12.5 0.02                              Escherichia coli KNK 437                                                                        0.2  6.2 6.2                                                                              25  100  100  0.39                              Enterobacter aerogenes ATCC 13048                                                               0.05 0.78                                                                              0.78                                                                             3.1 6.2  12.5 0.02                              Klebsiella pneumoniae ATCC 8045                                                                 0.02 0.2 0.2                                                                              3.1 6.2  6.2  0.02                              Providencia stuartii CMX 640                                                                    0.78 25  25 25  >100 >100 1.56                              Pseudomonas aeruginosa BMH 10                                                                   0.1  6.2 6.2                                                                              6.2 25   25   0.2                               Pseudomonas aeruginosa A5007                                                                    0.1  6.2 6.2                                                                              6.2 50   25   0.39                              Pseudomonas aeruginosa K799/WT                                                                  0.1  3.1 3.1                                                                              6.2 25   25   0.2                               Pseudomonas aeruginosa K799/61                                                                  0.02 0.39                                                                              0.39                                                                             0.05                                                                              6.2  25   0.05                              Pseudomonas aeruginosa 5263                                                                     12.5 --  -- --  --   --   50                                Pseudomonas aeruginosa 2862                                                                     25   --  -- --  --   --   25                                Pseudomonas cepacia 296I                                                                        3.1  25  25 3.1 100  100  3.1                               Acinetobacter calcoaceticus CMX 669                                                             0.39 0.78                                                                              0.78                                                                             0.78                                                                              50   25   0.2                               __________________________________________________________________________                 Example number                                                   Organism     158     159  160      161 162                                    __________________________________________________________________________    S. aureus ATCC 6538P                                                                       0.2     0.2  0.2      0.05                                                                              0.1                                    S. aureus A5177                                                                            0.39    0.39 0.39     0.1 0.1                                    S. aureus A-5278                                                                           0.78    0.2  0.2      0.1 0.1                                    S. aureus 642A                                                                             0.2     0.39 0.2      0.1 0.2                                    S. aureus NCTC 10649                                                                       0.2     0.2  0.2      0.05                                                                              0.1                                    S. aureus CMX 553                                                                          0.39    0.39 0.39     0.1 0.2                                    S. aureus 1775                                                                             100     >100 100      100 >100                                   S. epidermidis 3519                                                                        0.39    0.39 0.39     0.1 0.2                                    M. luteus ATCC 9341                                                                        3.1     25   6.2      3.1 6.2                                    M. luteus ATCC 4698                                                                        1.56    12.5 0.78     3.1 3.1                                    E. faecium ATCC 8043                                                                       1.56    6.2  3.1      0.78                                                                              0.78                                   S.s bovis A5169                                                                            6.2     12.5 6.2      1.56                                                                              1.56                                   S. agalactaciae CMX 508                                                                    1.56    3.1  1.56     0.39                                                                              0.78                                   S. pyrogenes EES61                                                                         1.56    3.1  1.56     0.39                                                                              0.39                                   S. pyrogenes CONST                                                                         1.56    3.1  1.56     0.39                                                                              0.39                                   S. pyrogenes 2548 INDUC                                                                    0.78    3.1  0.78     0.1 0.2                                    E. coli JUHL 0.02    0.39 0.39     0.02                                                                              0.02                                   E. coli SS   0.01    0.02 .005     .005                                                                              .005                                   E. coli DC-2 0.39    6.2  25       0.2 0.39                                   E. coli H560 0.02    0.39 3.1      0.02                                                                              0.02                                   E. coli KNK 437                                                                            0.39    6.2  25       0.2 0.39                                   E. aerogenes ATCC 13048                                                                    0.1     0.78 12.5     0.05                                                                              0.05                                   K. pneumoniae ATCC 8045                                                                    0.05    0.2  1.56     0.01                                                                              0.02                                   P. stuartii CMX 640                                                                        3.1     25   >100     1.56                                                                              1.56                                   P. aeruginosa BMH 10                                                                       0.2     3.1  12.5     0.2 0.2                                    P. aeruginosa A5007                                                                        0.2     6.2  25       0.2 0.39                                   P. aeruginosa K799/WT                                                                      0.2     3.1  12.5     0.2 0.39                                   P. aeruginosa K799/61                                                                      0.05    0.39 3.1      0.05                                                                              0.05                                   P. aeruginosa 5263                                                                         50      >100 >100     100 100                                    P. aeruginosa 2862                                                                         50      >100 >100     100 100                                    P. cepacia 296I                                                                            3.1     25   >100     3.1 6.2                                    A. calcoaceticus CMX 669                                                                   0.2     0.78 3.1      0.05                                                                              0.1                                    __________________________________________________________________________                    Example number                                                Organism        163  164       165  166                                       __________________________________________________________________________    S. aureus ATCC 6538P                                                                          1.56 0.78      6.2  0.39                                      S. aureus A5177 1.56 1.56      6.2  1.56                                      S. aureus A-5278                                                                              1.56 1.56      6.2  1.56                                      S. aureus 642A  1.56 1.56      6.2  1.56                                      S. aureus NCTC 10649                                                                          0.78 1.56      6.2  0.39                                      S. aureus CMX 553                                                                             1.56 1.56      6.2  3.1                                       S. aureus 1775  100  50        >100 >100                                      S. epidermidis 3519                                                                           1.56 1.56      6.2  0.78                                      M. luteus ATCC 9341                                                                           25   12.5      >100 50                                        M. luteus ATCC 4698                                                                           12.5 6.2       >100 25                                        E. faecium ATCC 8043                                                                          12.5 12.5      >100 12.5                                      S.s bovis A5169 50   12.5      >100 25                                        S. agalactaciae CMX 508                                                                       12.5 12.5      >100 3.1                                       S. pyrogenes EES61                                                                            12.5 12.5      >100 1.56                                      S. pyrogenes CONST                                                                            12.5 12.5      >100 1.56                                      S. pyrogenes 2548 INDUC                                                                       12.5 12.5      >100 1.56                                      E. coli JUHL    0.2  0.05      3.1  0.78                                      E. coli SS      0.1  0.02      0.2  0.05                                      E. coli DC-2    6.2  1.56      >100 12.5                                      E. coli H560    0.1  0.1       3.1  0.78                                      E. coli KNK 437 3.1  1.56      >100 6.2                                       E. aerogenes ATCC 13048                                                                       0.39 0.05      3.1  3.1                                       K. pneumoniae ATCC 8045                                                                       0.1  0.05      0.39 1.56                                      P. stuartii CMX 640                                                                           50   12.5      >100 >100                                      P. aeruginosa BMH 10                                                                          1.56 0.39      50   3.1                                       P. aeruginosa A5007                                                                           3.1  0.39      25   6.2                                       P. aeruginosa K799/WT                                                                         3.1  0.39      25   6.2                                       P. aeruginosa K799/61                                                                         1.56 0.1       3.1  0.39                                      P. aeruginosa 5263                                                                            100  100            >100                                      P. aeruginosa 2862                                                                            >100 100            >100                                      P. cepacia 296I 12.5 3.1       25   >100                                      A. calcoaceticus CMX 669                                                                      0.39 0.39      6.2  3.1                                       __________________________________________________________________________                 Example number                                                   Organism     167  168  169  170  171 172  173                                 __________________________________________________________________________    S. aureus ATCC 6538P                                                                       0.78 0.78 0.1  0.05 0.1 50   1.56                                S. aureus A5177                                                                            3.1  3.1  0.2  0.1  0.1 100  6.2                                 S. aureus A-5278                                                                           1.56 3.1  0.2  0.1  0.1 50   6.2                                 S. aureus 642A                                                                             3.1  3.1  0.39 0.1  0.2 100  12.5                                S. aureus NCTC 10649                                                                       0.78 0.78 0.2  0.05 0.1 50   1.56                                S. aureus CMX 553                                                                          6.2  6.2  0.39 0.2  0.2 >100 12.5                                S. aureus 1775                                                                             >100 >100 25   100  50  >100 >100                                S. epidermidis 3519                                                                        3.1  3.1  0.39 0.2  0.2 50   6.2                                 M. luteus ATCC 9341                                                                        50   50   3.1  12.5 3.1 >100 >100                                M. luteus ATCC 4698                                                                        50   50   0.39 1.56 0.78                                                                              >100 100                                 E. faecium ATCC 8043                                                                       12.5 12.5 1.56 0.78 0.78                                                                              >100 50                                  S.s bovis A5169                                                                            12.5 12.5 3.1  6.2  1.56                                                                              >100 25                                  S. agalactaciae CMX 508                                                                    6.2  6.2  0.78 0.78 0.78                                                                              >100 12.5                                S. pyrogenes EES61                                                                         6.2  6.2  0.78 0.78 0.78                                                                              >100 12.5                                S. pyrogenes CONST                                                                         3.1  3.1  0.39 0.78 0.78                                                                              >100 12.5                                S. pyrogenes 2548 INDUC                                                                    1.56 1.56 0.39 0.39 0.39                                                                              >100 6.2                                 E. coli JUHL 1.56 0.78 0.78 --   0.02                                                                              6.2  6.2                                 E. coli SS   0.05 0.05 0.005                                                                              0.001                                                                              0.001                                                                             0.39 0.1                                 E. coli DC-2 25   25   12.5 3.1  0.78                                                                              >100 >100                                E. coli H560 1.56 0.78 0.78 0.1  0.02                                                                              6.2  3.1                                 E. coli KNK 437                                                                            25   12.5 6.2  1.56 0.39                                                                              >100 100                                 E. aerogenes ATCC 13048                                                                    3.1  3.1  3.1  0.39 0.1 6.2  25                                  K. pneumoniae ATCC 8045                                                                    3.1  3.1  0.39 0.05 0.01                                                                              3.1  3.1                                 P. stuartii CMX 640                                                                        100  100  25   6.2  6.2 >100 >100                                P. aeruginosa BMH 10                                                                       12.5 3.1  3.1  0.78 0.2 50   50                                  P. aeruginosa A5007                                                                        6.2  12.5 3.1  0.78 0.39                                                                              50   50                                  P. aeruginosa K799/WT                                                                      6.2  6.2  3.1  0.78 0.39                                                                              100  100                                 P. aeruginosa K799/61                                                                      1.56 1.56 0.39 0.05 0.05                                                                              6.2  3.1                                 P. aeruginosa 5263                                                                         >100 >100 >100 >100 50  >100 >100                                P. aeruginosa 2862                                                                         >100 >100 >100 >100 50  >100 >100                                P. cepacia 296I                                                                            100  >100 25   6.2  6.2 >100 >100                                A. calcoaceticus CMX 669                                                                   12.5 12.5 3.1  0.2  0.05                                                                              25   25                                  __________________________________________________________________________

                                      TABLE 15                                    __________________________________________________________________________    In Vitro Antibacterial Activity (MIC Values in μg/ml)                                                                     Cipro-                         Organisms         Ex. 253                                                                             Ex. 254                                                                             Ex. 255                                                                             Ex. 256                                                                            Ex. 257                                                                             floxacin                       __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                        0.01  0.002 0.01  0.05 0.01  0.2                            Staph. aureus A5177                                                                             0.01  0.005 0.02  0.1  0.01  0.39                           Staph. aureus 5278                                                                              0.01  0.005 0.02  0.1  0.01  0.39                           Staph. aureus 642A                                                                              0.02  0.002 0.05  0.1  0.02  0.39                           Staph. aureus NCTC10649                                                                         0.01  0.002 0.02  0.05 0.02  0.39                           Staph. aureus CMX 553                                                                           0.02  0.01  0.02  0.1  0.02  0.78                           Staph. aureus 1775 Cipro.R.                                                                     1.56  0.39  1.56  6.2  0.78  >100                           Staph. epidermidis 3519                                                                         0.01  0.005 0.02  0.1  0.01  0.39                           M. luteus ATCC 9341                                                                             0.05  0.01  0.1   0.78 0.05  1.56                           M. luteus ATCC 4698                                                                             0.02  0.01  0.1   0.78 0.05  0.78                           Entero. faecium ATTC 8043                                                                       0.02  0.01  0.1   0.2  0.02  0.39                           Strep. bovis A5169                                                                              0.02  0.002 0.05  0.78 0.02  1.56                           Strep. agalactiae CMX 508                                                                       0.02  0.002 0.02  0.39 0.02  0.39                           Strep. pyogenes EES61                                                                           0.02  0.002 0.05  0.39 0.02  0.78                           Strep. pyogenes 930 CONST                                                                       0.02  0.002 0.05  0.2  0.02  0.78                           Strep. pyogenes 2458 INDUC                                                                      0.01  0.002 0.05  0.2  0.02  0.39                           Escherichia coli Juhl                                                                           0.002 0.005 0.005 0.01 0.002 0.01                           E. coli SS        0.0005                                                                              0.0005                                                                              0.0005                                                                              0.002                                                                              0.0005                                                                              0.005                          E. coli DC-2      0.02  0.05  0.1   0.2  0.02  0.2                            E. coli H560      0.002 0.002 0.01  0.02 0.002 0.01                           E. coli KNK 437   0.02  0.05  0.1   0.2  0.02  0.2                            Enter. aerogenes ATCC 13048                                                                     0.005 0.01  0.05  0.05 0.01  0.02                           Klebsiella pneumoniae ATCC 8045                                                                 0.002 0.005 0.005 0.01 0.002 0.02                           Providencia stuartii CMX 640                                                                    0.2   0.39  0.78  1.56 0.2   0.78                           Pseudomonas cepacia 296I                                                                        0.39  0.39  0.78  0.78 0.39  3.1                            P. aeruginosa BMH 10                                                                            0.05  0.05  0.2   0.2  0.02  0.1                            P. aeruginosa A5007                                                                             0.05  0.1   0.2   0.2  0.05  0.1                            P. aeruginosa K799/WT                                                                           0.05  0.1   0.2   0.2  0.05  0.1                            P. aeruginosa K799/61                                                                           0.01  0.01  0.05  0.05 0.01  0.02                           P. aeruginosa 5263                                                                              0.78  1.56  3.1   12.5 0.39  12.5                           P. aeruginosa 2863                                                                              0.78  1.56  1.56  12.5 0.39  12.5                           Acinetobacter calcoaceticus CMX 669                                                             0.01  0.05  0.01  0.1  0.02  0.39                           Myco. smegmatis ATCC 114                                                                        0.02  0.1   0.2   0.78 0.2   0.78                           Nocardia asteroides ATCC 9970                                                                   0.2   0.1   0.2   0.39 0.2   12.5                           Candida albicans CCH 442                                                                        >100  >100  >100  >100 >100  >100                           __________________________________________________________________________                                                   Cipro-                         Organisms         Ex. 258                                                                             Ex. 259                                                                             Ex. 260                                                                             Ex. 261                                                                            Ex. 262                                                                             floxacin                       __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                        0.1   0.05  0.05  0.05 0.05  0.2                            Staph. aureus A5177                                                                             0.1   0.1   0.1   0.05 0.05  0.39                           Staph. aureus 5278                                                                              0.1   0.1   0.1   0.05 0.05  0.39                           Staph. aureus 642A                                                                              0.1   0.1   0.1   0.05 0.05  0.39                           Staph. aureus NCTC10649                                                                         0.1   0.1   0.05  0.05 0.05  0.39                           Staph. aureus CMX 553                                                                           0.2   0.2   0.1   0.05 0.1   0.78                           Staph. aureus 1775 Cipro.R.                                                                     6.2   12.5  6.2   0.78 3.1   >100                           Staph. epidermidis 3519                                                                         0.1   0.1   0.1   0.05 0.05  0.39                           Entero. faecium ATTC 8043                                                                       0.2   0.2   0.1   0.1  0.1   0.39                           Strep. bovis A5169                                                                              0.39  0.78  0.1   0.2  0.1   1.56                           Strep. agalactiae CMX 508                                                                       0.2   0.2   0.1   0.1  0.05  0.39                           Strep. pyogenes EES61                                                                           0.39  0.2   0.1   0.1  0.05  0.78                           Strep. pyogenes 930 CONST                                                                       0.39  0.2   0.1   0.1  0.05  0.78                           Strep. pyogenes 2458 INDUC                                                                      0.2   0.2   0.05  0.1  0.05  0.39                           M. luteus ATCC 9341                                                                             0.39  0.2   0.2   0.2  0.1   1.56                           M. luteus ATCC 4698                                                                             0.2   0.2   0.2   0.1  0.05  0.78                           Escherichia coli Juhl                                                                           0.01  0.01  0.1   0.78 0.02  0.01                           E. coli SS        0.005 0.001 0.02  0.05 <0.005                                                                              0.005                          E. coli DC-2      0.2   0.2   1.56  100  0.2   0.2                            E. coli H560      0.01  0.01  0.2   0.39 0.01  0.01                           E. coli KNK 437   0.2   0.2   1.56  12.5 0.1   0.2                            Enter. aerogenes ATCC 13048                                                                     0.05  0.02  0.39  1.56 0.1   0.02                           Klebsiella pneumoniae ATCC 8045                                                                 0.01  0.01  0.2   0.39 0.05  0.02                           Providencia stuartii CMX 640                                                                    1.56  0.78  12.5  100  1.56  0.78                           P. aeruginosa BMH 10                                                                            0.2   0.2   1.56  50   0.2   0.1                            P. aeruginosa A5007                                                                             0.39  0.2   3.1   50   0.39  0.1                            P. aeruginosa K799/WT                                                                           0.39  0.2   1.56  50   0.39  0.1                            P. aeruginosa K799/61                                                                           0.05  0.02  0.39  0.39 0.1   0.02                           Pseudomonas cepacia 296I                                                                        3.1   1.56  12.5  50   3.1   3.1                            Acinetobacter calcoaceticus CMX 669                                                             0.05  0.1   0.78  0.39 0.2   0.39                           P. aeruginosa 5263                                                                              6.2   3.1   50    >100 3.1   12.5                           P. aeruginosa 2863                                                                              6.2   3.1   25    >100 3.1   12.5                           Candida albicans CCH 442                                                                        >100  >100  >100  >100 >100  >100                           Myco. smegmatis ATCC 114                                                                        0.78  0.2   1.56  50   1.56  0.78                           Nocardia asteroides ATCC 9970                                                                   12.5  1.56  1.56  50   0.78  12.5                           __________________________________________________________________________                                                   Cipro-                         Organisms         Ex. 263                                                                             Ex. 264                                                                             Ex. 265                                                                             Ex. 266                                                                            Ex. 267                                                                             floxacin                       __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                        0.01  0.02  0.02  0.02 0.1   0.2                            Staph. aureus A5177                                                                             0.02  0.05  0.1   0.05 0.1   0.39                           Staph. aureus 5278                                                                              0.02  0.05  0.05  0.05 0.1   0.39                           Staph. aureus 642A                                                                              0.02  0.1   0.1   0.1  0.2   0.39                           Staph. aureus NCTC10649                                                                         0.01  0.02  0.1   0.02 0.1   0.39                           Staph. aureus CMX 553                                                                           0.05  0.1   0.05  0.1  0.2   0.78                           Staph. aureus 1775 Cipro.R.                                                                     .39   3.1   0.78  0.39 6.2   >100                           Staph. epidermidis 3519                                                                         0.02  0.05  0.1   0.05 0.1   0.39                           Entero. faecium ATTC 8043                                                                       0.05  0.1   0.1   0.2  0.39  0.39                           Strep. bovis A5169                                                                              0.05  0.1   0.2   0.2  0.78  1.56                           Strep. agalactiae CMX 508                                                                       0.02  0.02  0.05  0.1  0.39  0.39                           Strep. pyogenes EES61                                                                           0.02  0.02  0.05  0.2  0.39  0.78                           Strep. pyogenes 930 CONST                                                                       0.02  0.05  0.1   0.2  0.78  0.78                           Strep. pyogenes 2458 INDUC                                                                      0.01  0.05  0.1   0.2  0.78  0.39                           M. luteus ATCC 9341                                                                             0.05  0.2   0.1   0.1  0.39  1.56                           M. luteus ATCC 4698                                                                             0.05  0.1   0.1   0.1  0.39  0.78                           Escherichia coli Juhl                                                                           0.02  0.02  0.78  0.1  0.02  0.01                           E. coli SS        0.002 0.005 0.05  0.005                                                                              0.002 0.005                          E. coli DC-2      0.1   0.2   0.78  0.78 0.2   0.2                            E. coli H560      0.01  0.02  1.56  0.1  0.02  0.01                           E. coli KNK 437   0.1   0.39  6.2   0.78 0.2   0.2                            Enter. aerogenes ATCC 13048                                                                     0.05  0.1   1.56  0.2  0.1   0.02                           Klebsiella pneumoniae ATCC 8045                                                                 0.02  0.1   0.39  0.2  0.02  0.02                           Providencia stuartii CMX 640                                                                    0.78  3.1   12.5  25   3.1   0.78                           P. aeruginosa BMH 10                                                                            0.2   0.39  3.1   1.56 0.78  0.1                            P. aeruginosa A5007                                                                             0.2   0.39  6.2   1.56 1.56  0.1                            P. aeruginosa K799/WT                                                                           0.2   0.39  6.2   1.56 0.78  0.1                            P. aeruginosa K799/61                                                                           0.05  0.1   0.78  0.2  0.1   0.02                           Pseudomonas cepacia 296I                                                                        0.78  3.1   6.2   3.1  3.1   3.1                            Acinetobacter calcoaceticus CMX 669                                                             0.1   0.2   1.56  0.78 0.05  0.39                           P. aeruginosa 5263                                                                              3.1   6.2   >100  50   25    12.5                           P. aeruginosa 2863                                                                              3.1   6.2   >100  25   12.5  12.5                           Candida albicans CCH 442                                                                        >100  >100  >100  >100 >100  >100                           Myco. smegmatis ATCC 114                                                                        0.2   0.2   25    3.1  0.2   0.78                           Nocardia asteroides ATCC 9970                                                                   0.2   3.1   12.5  1.56 6.2   12.5                           __________________________________________________________________________                                                   Cipro-                         Organisms         Ex. 268                                                                             Ex. 269                                                                             Ex. 270                                                                             Ex. 271                                                                            Ex. 272                                                                             floxacin                       __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                        0.05  0.01  0.02  0.01 0.1   0.2                            Staph. aureus A5177                                                                             0.1   0.02  0.02  0.02 0.1   0.39                           Staph. aureus 5278                                                                              0.1   0.02  0.02  0.01 0.1   0.39                           Staph. aureus 642A                                                                              0.1   0.05  0.02  0.01 0.1   0.39                           Staph. aureus NCTC10649                                                                         0.05  0.02  0.01  0.005                                                                              0.1   0.39                           Staph. aureus CMX 553                                                                           0.1   0.05  0.02  0.02 0.1   0.78                           Staph. aureus 1775 Cipro.R.                                                                     6.2   0.78  0.39  0.2  1.56  >100                           Staph. epidermidis 3519                                                                         0.1   0.05  0.02  0.02 0.1   0.39                           Entero. faecium ATTC 8043                                                                       0.1   0.1   0.1   0.05 0.39  0.39                           Strep. bovis A5169                                                                              0.1   0.05  0.2   0.05 0.78  1.56                           Strep. agalactiae CMX 508                                                                       0.1   0.05  0.1   0.05 0.39  0.39                           Strep. pyogenes EES61                                                                           0.1   0.05  0.1   0.05 0.39  0.78                           Strep. pyogenes 930 CONST                                                                       0.1   0.05  0.2   0.05 0.39  0.78                           Strep. pyogenes 2458 INDUC                                                                      0.05  0.02  0.2   0.05 0.39  0.39                           M. luteus ATCC 9341                                                                             0.2   0.1   0.2   0.02 0.39  1.56                           M. luteus ATCC 4698                                                                             0.1   0.1   0.05  0.02 0.39  0.78                           Escherichia coli Juhl                                                                           0.01  0.01  0.1   0.02 0.02  0.01                           E. coli SS        0.005 0.001 0.005 0.001                                                                              0.001 0.005                          E. coli DC-2      0.2   0.1   0.39  0.2  0.39  0.2                            E. coli H560      0.02  0.01  0.1   0.05 0.02  0.01                           E. coli KNK 437   0.2   0.1   0.39  0.2  0.39  0.2                            Enter. aerogenes ATCC 13048                                                                     0.05  0.05  0.39  0.02 0.01  0.02                           Klebsiella pneumoniae ATCC 8045                                                                 0.02  0.01  0.05  0.02 0.02  0.02                           Providencia stuartii CMX 640                                                                    1.56  0.78  1.56  0.2  1.56  0.78                           P. aeruginosa BMH 10                                                                            0.2   0.2   0.78  0.2  0.78  0.1                            P. aeruginosa A5007                                                                             0.39  0.39  1.56  0.2  0.78  0.1                            P. aeruginosa K799/WT                                                                           0.39  0.2   0.78  0.2  0.78  0.1                            P. aeruginosa K799/61                                                                           0.05  0.05  0.1   0.02 0.02  0.02                           Pseudomonas cepacia 296I                                                                        3.1   1.56  3.1   0.1  1.56  3.1                            Acinetobacter calcoaceticus CMX 669                                                             0.1   0.02  0.2   0.01 0.05  0.39                           P. aeruginosa 5263                                                                              3.1   3.1   50    6.2  12.5  12.5                           P. aeruginosa 2863                                                                              3.1   3.1   25    6.2  6.2   12.5                           Candida albicans CCH 442                                                                        >100  >100  >100  >100 >100  >100                           Myco. smegmatis ATCC 114                                                                        0.78  0.1   0.78  0.78 1.56  0.78                           Nocardia asteroides ATCC 9970                                                                   3.1   0.39  1.56  0.78 1.56  12.5                           __________________________________________________________________________                                                   Cipro-                         Organisms         Ex. 273                                                                             Ex. 274                                                                             Ex. 275                                                                             Ex. 276                                                                            Ex. 277                                                                             floxacin                       __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                        0.2   0.1   0.05  0.02 0.01  0.2                            Staph. aureus A5177                                                                             0.2   0.2   0.05  0.05 0.02  0.39                           Staph. aureus 5278                                                                              0.2   0.2   0.05  0.02 0.02  0.39                           Staph. aureus 642A                                                                              0.39  0.2   0.1   0.05 0.02  0.39                           Staph. aureus NCTC10649                                                                         0.2   0.1   0.05  0.02 0.02  0.39                           Staph. aureus CMX 553                                                                           0.39  0.39  0.1   0.05 0.05  0.78                           Staph. aureus 1775 Cipro.R.                                                                     6.2   6.2   3.1   1.56 1.56  >100                           Staph. epidermidis 3519                                                                         0.2   0.2   0.05  0.02 0.02  0.39                           Entero. faecium ATTC 8043                                                                       0.39  0.78  0.2   0.1  0.05  0.39                           Strep. bovis A5169                                                                              0.78  0.78  0.39  0.1  0.1   1.56                           Strep. agalactiae CMX 508                                                                       0.39  0.78  0.2   0.05 0.05  0.39                           Strep. pyogenes EES61                                                                           0.39  0.78  0.2   0.05 0.05  0.78                           Strep. pyogenes 930 CONST                                                                       0.2   0.78  0.1   0.05 0.05  0.78                           Strep. pyogenes 2458 INDUC                                                                      0.2   0.78  0.1   0.05 0.05  0.39                           M. luteus ATCC 9341                                                                             0.78  0.78  0.2   0.1  0.05  1.56                           M. luteus ATCC 4698                                                                             0.78  0.39  0.2   0.1  0.05  0.78                           Escherichia coli Juhl                                                                           0.05  0.01  0.02  0.005                                                                              0.005 0.01                           E. coli SS        0.005 0.01  0.005 0.002                                                                              0.0005                                                                              0.005                          E. coli DC-2      0.02  0.2   0.2   0.05 0.05  0.2                            E. coli H560      0.02  0.05  0.02  0.005                                                                              0.005 0.01                           E. coli KNK 437   0.39  0.2   0.2   0.05 0.05  0.2                            Enter. aerogenes ATCC 13048                                                                     0.1   0.02  0.05  0.02 0.01  0.02                           Klebsiella pneumoniae ATCC 8045                                                                 0.05  0.01  0.01  0.005                                                                              0.005 0.02                           Providencia stuartii CMX 640                                                                    3.1   3.1   1.56  0.39 0.2   0.78                           P. aeruginosa BMH 10                                                                            0.39  0.2   0.2   0.1  0.05  0.1                            P. aeruginosa A5007                                                                             0.39  0.39  0.39  0.2  0.05  0.1                            P. aeruginosa K799/WT                                                                           0.39  0.39  0.2   0.1  0.05  0.1                            P. aeruginosa K799/61                                                                           0.1   0.05  0.05  0.02 0.01  0.02                           Pseudomonas cepacia 296I                                                                        6.2   3.1   3.1   1.56 0.78  3.1                            Acinetobacter calcoaceticus CMX 669                                                             0.2   0.2   0.1   0.02 0.02  0.39                           P. aeruginosa 5263                                                                              12.5  12.5  6.2   1.56 1.56  12.5                           P. aeruginosa 2863                                                                              6.2   6.2   3.1   1.56 1.56  12.5                           Candida albicans CCH 442                                                                        >100  >100  >100  >100 >100  >100                           Myco. smegmatis ATCC 114                                                                        6.2   0.2   0.78  0.78 0.05  0.78                           Nocardia asteroides ATCC 9970                                                                   6.2   3.1   0.78  0.39 0.39  12.5                           __________________________________________________________________________                                                   Cipro-                         Organisms         Ex. 278                                                                             Ex. 279                                                                             Ex. 280                                                                             Ex. 281                                                                            Ex. 282                                                                             floxacin                       __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                        0.39  3.1   0.39  0.39 0.78  0.2                            Staph. aureus A5177                                                                             0.39  25    0.78  0.39 3.1   0.39                           Staph. aureus 5278                                                                              0.39  12.5  0.78  0.39 3.1   0.39                           Staph. aureus 642A                                                                              0.39  25    0.78  1.56 3.1   0.39                           Staph. aureus NCTC10649                                                                         0.39  25    0.78  0.39 1.56  0.39                           Staph. aureus CMX 553                                                                           0.78  12.5  0.78  0.39 3.1   0.78                           Staph. aureus 1775 Cipro.R.                                                                     25    >100  >100  25   25    >100                           Staph. epidermidis 3519                                                                         0.78  25    0.78  0.39 3.1   0.39                           Entero. faecium ATTC 8043                                                                       1.56  50    6.2   3.1  3.1   0.39                           Strep. bovis A5169                                                                              6.2   100   25    3.1  3.1   1.56                           Strep. agalactiae CMX 508                                                                       3.1   100   12.5  1.56 0.78  0.39                           Strep. pyogenes EES61                                                                           3.1   100   12.5  1.56 0.78  0.78                           Strep. pyogenes 930 CONST                                                                       3.1   50    6.2   1.56 0.78  0.78                           Strep. pyogenes 2458 INDUC                                                                      3.1   100   12.5  1.56 0.78  0.39                           M. luteus ATCC 9341                                                                             6.2   100   25         6.2   1.56                           M. luteus ATCC 4698                                                                             3.1   50    12.5       6.2   0.78                           Escherichia coli Juhl                                                                           0.2   6.2   1.56  0.2  3.1   0.01                           E. coli SS        0.01  0.78  = <0.39                                                                             0.02 0.2   0.005                          E. coli DC-2      1.56  50    25    1.56 6.2   0.2                            E. coli H560      0.1   6.2   1.56  0.2  3.1   0.01                           E. coli KNK 437   0.78  25    12.5  3.1  6.2   0.2                            Enter. aerogenes ATCC 13048                                                                     0.2   6.2   3.1   0.39 6.2   0.02                           Klebsiella pneumoniae ATCC 8045                                                                 0.1   3.1   = <0.39                                                                             0.2  3.1   0.02                           Providencia stuartii CMX 640                                                                    6.2   100   25    3.1  25    0.78                           P. aeruginosa BMH 10                                                                            1.56  25    6.2   1.56 6.2   0.1                            P. aeruginosa A5007                                                                             3.1   25    6.2   1.56 6.2   0.1                            P. aeruginosa K799/WT                                                                           3.1   25    6.2   1.56 6.2   0.1                            P. aeruginosa K799/61                                                                           0.2   6.2   = <0.39                                                                             0.39 3.1   0.02                           Pseudomonas cepacia 296I                                                                        6.2   100   6.2   3.1  25    3.1                            Acinetobacter calcoaceticus CMX 669                                                             0.2   6.2   3.1   1.56 12.5  0.39                           P. aeruginosa 5263                                                                              50    >100        12.5 25    12.5                           P. aeruginosa 2863                                                                              25    >100        12.5 25    12.5                           Candida albicans CCH 442                       >100                           Myco. smegmatis ATCC 114                       0.78                           Nocardia asteroides ATCC 9970                  12.5                           __________________________________________________________________________    Organisms          Ex. 284                                                                            Ex. 285   Ex. 296                                                                            Ciprofloxacin                          __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                         0.78 0.78      0.02 0.2                                    Staph. aureus A5177                                                                              1.56 0.78      0.05 0.39                                   Staph. aureus 5278 0.78 0.78      0.05 0.39                                   Staph. aureus 642A 1.56 0.78      0.05 0.39                                   Staph. aureus NCTC10649                                                                          0.78 1.56      0.05 0.39                                   Staph. aureus CMX 553                                                                            3.1  0.78      0.05 0.78                                   Staph. aureus 1775 Cipro.R.                                                                      25   >100      3.1  >100                                   Staph. epidermidis 3519                                                                          1.56 1.56      0.05 0.39                                   Entero. faecium ATTC 8043                                                                        3.1  3.1       0.1  0.39                                   Strep. bovis A5169 na   25        0.1  1.56                                   Strep. agalactiae CMX 508                                                                        3.1  12.5      0.05 0.39                                   Strep. pyogenes EES61                                                                            3.1  12.5      0.05 0.78                                   Strep. pyogenes 930 CONST                                                                        12.5 12.5      0.05 0.78                                   Strep. pyogenes 2458 INDUC                                                                       6.2  12.5      0.05 0.39                                   M. luteus ATCC 9341                                                                              12.5 50        0.1  1.56                                   M. luteus ATCC 4698                                                                              6.2  12.5      0.1  0.78                                   Escherichia coli Juhl                                                                            1.56 0.39      0.01 0.01                                   E. coli SS         0.1  0.1       0.002                                                                              0.005                                  E. coli DC-2       12.5 3.1       0.2  0.2                                    E. coli H560       3.1  0.39      0.01 0.01                                   E. coli KNK 437    12.5 3.1       0.05 0.2                                    Enter. aerogenes ATCC 13048                                                                      3.1  0.39      0.5  0.02                                   Klebsiella pneumoniae ATCC 8045                                                                  1.56 0.2       0.01 0.02                                   Providencia stuartii CMX 640                                                                     12.5 12.5      3.1  0.78                                   P. aeruginosa BMH 10                                                                             12.5 1.56      0.1  0.1                                    P. aeruginosa A5007                                                                              12.5 1.56      0.39 0.1                                    P. aeruginosa K799/WT                                                                            12.5 1.56      0.39 0.1                                    P. aeruginosa K799/61                                                                            1.56 0.39      0.1  0.02                                   Pseudomonas cepacia 296I                                                                         12.5 25        0.78 3.1                                    Acinetobacter calcoaceticus CMX 669                                                              3.1  0.39      0.02 0.39                                   P. aeruginosa 5263 50   >100      3.1  12.5                                   P. aeruginosa 2863 50   >100      3.1  12.5                                   Candida albicans CCH 442                                                                         >100           >100 >100                                   Myco. smegmatis ATCC 114                                                                         25             0.05 0.78                                   Nocardia asteroides ATCC 9970                                                                    25             3.1  12.5                                   __________________________________________________________________________

                                      TABLE 16                                    __________________________________________________________________________    In Vitro Antibacterial Activity (MIC Values in μg/ml)                      __________________________________________________________________________    Organisms      Ex. 298                                                                              Ex. 299                                                                              Ex. 300                                                                              Ex. 301                                                                              Ex. 302                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.02   0.05   0.001  0.002  0.002  0.2                         Staph. aureus A5177                                                                          0.02   0.05   0.001  0.005  0.005  0.39                        Staph. aureus 5278                                                                           0.05   0.05   0.001  0.005  0.005  0.39                        Staph. aureus 642A                                                                           0.1    0.05   0.001  0.01   0.01   0.39                        Staph. aureus NCTC 10649                                                                     0.02   0.05   0.001  0.002  0.002  0.39                        Staph. aureus CMX 553                                                                        0.1    0.1    0.002  0.01   0.1    0.78                        Staph. aureus 1775 Cipro. R.                                                                 1.56   0.78   0.05   0.2    0.39   >100                        Staph. epidermidis 3519                                                                      0.05   0.05   0.001  0.005  0.005  0.39                        Entero. faecium ATCC 8043                                                                    0.2    0.1    0.001  0.01   0.01   0.39                        Strep. bovis A5169                                                                           0.39   0.39   0.001  0.005  0.01   1.56                        Strep. agalactiae CMX 508                                                                    0.2    0.1    0.001  0.001  0.005  0.39                        Strep. pyogenes EES61                                                                        0.2    0.1    0.001  0.001  0.005  0.78                        Strep. pyogenes 930 CONST                                                                    0.1    0.1    0.001  0.002  0.005  0.78                        Strep. pyogenes 2548 INDUC                                                                   0.1    0.1    0.001  0.002  0.005  0.39                        M. luteus ATCC 9341                                                                          0.2    0.2    0.01   0.02   0.01   1.56                        M. luteus ATCC 4698                                                                          0.1    0.1    0.005  0.02   0.01   0.78                        Escherichia coli Juhl                                                                        0.02   0.02   0.001  0.01   0.001  0.01                        E. coli SS     0.002  0.005                0.0005 0.005                       E. coli DC-2   0.2    0.39   0.02   0.05   0.05   0.2                         E. coli H560   0.02   0.02   0.002  0.01   0.001  0.01                        E. coli KNK 437                                                                              0.2    0.2    0.02   0.1    0.1    0.2                         Enter. aerogenes ATCC 13048                                                                  0.1    0.1    0.01   0.02   0.01   0.02                        Klebs. pneunoniae ATCC 8045                                                                  0.05   0.02   0.005  0.01   0.001  0.02                        Providencia stuartii CMX 640                                                                 3.1    3.1    0.2    0.39   0.78   0.78                        P. aeruginosa BMH 10                                                                         0.39   0.39   0.02   0.05   0.1    0.1                         P. aeruginosa A5007                                                                          0.39   0.39   0.05   0.2    0.2    0.1                         P. aeruginosa K799/WT                                                                        0.39   0.39   0.05   0.2    0.2    0.1                         P. aeruginosa K799/61                                                                        0.1    0.05   0.01   0.02   0.02   0.02                        Pseudomonas cepacia 296I                                                                     3.1    1.56   0.78   1.56   1.56   3.1                         Acinetob. calcoaceticus CMX 669                                                              0.05   0.05   0.01   0.05   0.02   0.78                        P. aeruginosa 5263                                                                           12.5   12.5   0.78   1.56   3.1    12.5                        P. aeruginosa 2862                                                                           12.5   12.5   1.56   3.1    6.2    12.5                        Candida albicans CCH 442                                                                     >100   >100   50     >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.39   0.2    0.1    0.2    0.002  0.78                        Nocardia asteroides ATCC 9970                                                                6.2    6.2    0.39   1.56   0.39   25                          __________________________________________________________________________    Organisms      Ex. 303                                                                              Ex. 304                                                                              Ex. 305                                                                              Ex. 306                                                                              Ex. 307                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.02   0.1    0.1    0.02   0.1    0.2                         Staph. aureus A5177                                                                          0.05   0.2    0.2    0.05   0.2    0.39                        Staph. aureus 5278                                                                           0.05   0.2    0.2    0.05   0.2    0.39                        Staph. aureus 642A                                                                           0.05   0.2    0.2    0.05   0.2    0.39                        Staph. aureus NCTC 10649                                                                     0.02   0.1    0.1    0.02   0.1    0.39                        Staph. aureus CMX 553                                                                        0.05   0.39   0.39   0.05   0.39   0.78                        Staph. aureus 1775 Cipro. R.                                                                 1.56   3.1    12.5   0.39   25     >100                        Staph. epidermidis 3519                                                                      0.01   0.2    0.2    0.02   0.2    0.39                        Entero. faecium ATCC 8043                                                                    0.05   0.78   0.39   0.1    0.39   0.39                        Strep. bovis A5169                                                                           0.1    0.78   0.39   0.2    1.56   1.56                        Strep. agalactiae CMX 508                                                                    0.1    0.39   0.2    0.1    0.78   0.39                        Strep. pyogenes EES61                                                                        0.1    0.78   0.39   0.1    0.78   0.78                        Strep. pyogenes 930 CONST                                                                    0.2    0.78   0.39   0.1    0.78   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.1    0.39   0.39   0.1    0.39   0.39                        M. luteus ATCC 9341                                                                          0.2    0.78   0.78   0.1    0.78   1.56                        M. luteus ATCC 4698                                                                          0.1    0.39   0.39   0.05   1.56   0.78                        Escherichia coli Juhl                                                                        0.1    0.1    0.39   0.78   0.05   0.01                        E. coli SS     0.02   0.005  0.01   0.05   0.02   0.005                       E. coli DC-2   1.56   0.78   1.56   3.1    0.39   0.2                         E. coli H560   0.05   0.1    0.39   0.39   0.1    0.01                        E. coli KNK 437                                                                              0.39   0.78   6.2    3.1    0.78   0.2                         Enter. aerogenes ATCC 13048                                                                  0.39   0.39   1.56   1.56   0.05   0.02                        Klebs. pneumoniae ATCC 8045                                                                  0.1    0.05   0.39   0.39   0.05   0.02                        Providencia stuartii CMX 640                                                                 0.78   12.5   50     12.5   3.1    0.78                        P. aeruginosa BMH 10                                                                         0.78   1.56   3.1    6.2    0.39   0.1                         P. aeruginosa A5007                                                                          1.56   3.1    3.1    6.2    0.39   0.1                         P. aeruginosa K799/WT                                                                        3.1    3.1    3.1    6.2    0.39   0.1                         P. aeruginosa K799/61                                                                        0.05   0.39   0.78   0.39   0.05   0.02                        Pseudomonas cepacia 296I                                                                     0.78   12.5   12.5   3.1    6.2    3.1                         Acinetob. calcoaceticus CMX 669                                                              0.1    0.39   3.1    1.56   0.78   0.78                        P. aeruginosa 5263                                                                           6.2    100    >100   >100   25     12.5                        P. aeruginosa 2862                                                                           50     100    >100   >100   25     12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.78   0.78   0.78   0.39   0.78   0.78                        Nocardia asteroides ATCC 9970                                                                0.78   12.5   25     6.2    25     25                          __________________________________________________________________________    Organisms      Ex. 308                                                                              Ex. 309                                                                              Ex. 310                                                                              Ex. 311                                                                              Ex. 312                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.002  0.005  0.005  0.002  0.01   0.2                         Staph. aureus A5177                                                                          0.002  0.005  0.005  0.002  0.02   0.39                        Staph. aureus 5278                                                                           0.002  0.005  0.005  0.002  0.02   0.39                        Staph. aureus 642A                                                                           0.002  0.01   0.01   0.005  0.02   0.39                        Staph. aureus NCTC 10649                                                                     0.0005 0.005  0.005  0.002  0.01   0.39                        Staph. aureus CMX 553                                                                        0.002  0.01   0.01   0.005  0.02   0.78                        Staph. aureus 1775 Cipro. R.                                                                 0.05   0.05   0.05   0.02   0.78   >100                        Staph. epidermidis 3519                                                                      0.002  0.01   0.005  0.005  0.02   0.39                        Entero. faecium ATCC 8043                                                                    0.01   0.2    0.02   0.01   0.02   0.39                        Strep. bovis A5169                                                                           0.002  0.005  0.005  0.002  0.005  1.56                        Strep. agalactiae CMX 508                                                                    0.002  0.005  0.002  0.001  0.005  0.39                        Strep. pyogenes EES61                                                                        0.002  0.005  0.005  0.001  0.005  0.78                        Strep. pyogenes 930 CONST                                                                    0.002  0.005  0.005  0.005  0.005  0.78                        Strep. pyogenes 2548 INDUC                                                                   0.002  0.005  0.005  0.005  0.005  0.39                        M. luteus ATCC 9341                                                                          0.01   0.0050 0.02   0.01   0.1    1.56                        M. luteus ATCC 4698                                                                          0.01   0.02   0.01   0.01   0.05   0.78                        Escherichia coli Juhl                                                                        0.01   0.05   0.01   0.01   0.05   0.01                        E. coli SS     0.0005 0.0005 0.001  0.0005 0.002  0.005                       E. coli DC-2   0.02   0.01   0.02   0.02   0.2    0.2                         E. coli H560   0.005  0.02   0.02   0.01   0.05   0.01                        E. coli KNK 437                                                                              0.05   0.2    0.1    0.05   0.39   0.2                         Enter. aerogenes ATCC 13048                                                                  0.05   0.1    0.1    0.05   0.2    0.02                        Klebs. pneumoniae ATCC 8045                                                                  0.01   0.02   0.005  0.01   0.1    0.02                        Providencia stuartii CMX 640                                                                 0.39   0.78   0.78   0.39   3.1    0.78                        P. aeruginosa BMH 10                                                                         0.1    0.39   0.2    0.1    0.39   0.1                         P. aeruginosa A5007                                                                          0.2    0.39   0.39   0.2    0.39   0.1                         P. aeruginosa K799/WT                                                                        0.2    0.39   0.39   0.2    0.39   0.1                         P. aeruginosa K799/61                                                                        0.05   0.1    0.1    0.05   0.05   0.02                        Pseudomonas cepacia 296I                                                                     1.56   3.1    1.56   1.56   --     3.1                         Acinetob. calcoaceticus CMX 669                                                              0.005  0.05   0.1    0.005  0.39   0.78                        P. aeruginosa 5263                                                                           1.56   12.5   6.2    1.56   3.1    12.5                        P. aeruginosa 2862                                                                           3.1    25     6.2    6.2    6.2    12.5                        Candida albicans CCH 442                                                                     12.5   100    6.2    50     >100   >100                        Myco. smegmatis ATCC 114                                                                     0.02   0.01   0.1    0.01   0.1    0.78                        Nocardia asteroides ATCC 9970                                                                0.2    0.39   0.2    0.39   6.2    25                          __________________________________________________________________________    Organisms      Ex. 313                                                                             Ex. 314                                                                             Ex. 316                                                                             Ex. 324                                                                             Ex. 325                                                                             Ex. 326                                                                             Cntl                       __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.005 0.005 0.005 0.02  0.01  0.05  0.2                        Staph. aureus A5177                                                                          0.005 0.005 0.005 0.05  0.01  0.1   0.39                       Staph. aureus 5278                                                                           0.005 0.005 0.005 0.05  0.02  0.1   0.39                       Staph. aureus 642A                                                                           0.005 0.005 0.01  0.02  0.02  0.1   0.39                       Staph. aureus NCTC 10649                                                                     0.002 0.005 0.005 0.02  0.01  0.05  0.39                       Staph. aureus CMX 553                                                                        0.01  0.01  0.01  0.05  0.02  0.2   0.78                       Staph. aureus 1775 Cipro. R.                                                                 0.1   0.05  0.1   1.56  0.78  25    >100                       Staph. epidermidis 3519                                                                      0.01  0.005 0.005 0.05  0.02  0.1   0.39                       Entero. faecium ATCC 8043                                                                    0.02  0.01  0.01  0.2   0.02  0.1   0.39                       Strep. bovis A5169                                                                           0.005 0.002 0.002 0.39  0.02  0.39  1.56                       Strep. agalactiae CMX 508                                                                    0.002 0.002 0.002 0.2   0.02  0.1   0.39                       Strep. pyogenes EES61                                                                        0.002 0.002 0.002 0.2   0.02  0.2   0.78                       Strep. pyogenes 930 CONST                                                                    0.005 0.005 0.002 0.2   0.02  0.2   0.78                       Strep. pyogenes 2548 INDUC                                                                   0.005 0.005 0.002 0.2   0.02  0.2   0.39                       M. luteus ATCC 9341                                                                          0.02  0.01  0.01  0.2   0.05  0.39  1.56                       M. luteus ATCC 4698                                                                          0.01  0.01  0.01  0.2   0.1   0.39  0.78                       Escherichia coli Juhl                                                                        0.01  0.01  0.01  0.05  0.02  0.05  0.01                       E. coli SS     0.002 0.001 0.002 0.005 0.0005                                                                              0.0005                                                                              0.005                      E. coli DC-2   0.1   0.1   0.1   0.78  0.2   0.39  0.2                        E. coli H560   0.01  0.02  0.02  0.05  0.02  0.1   0.01                       E. coli KNK 437                                                                              0.1   0.2   0.1   0.39  0.1   0.39  0.2                        Enter. aerogenes ATCC 13048                                                                  0.05  0.05  0.05  0.2   0.05  0.39  0.02                       Klebs. pneumoniae ATCC 8045                                                                  0.01  0.01  0.01  0.05  0.01  0.01  0.02                       Providencia stuartii CMX 640                                                                 0.39  1.56  0.78  3.1   1.56  3.1   0.78                       P. aeruginosa BMH 10                                                                         0.2   0.39  0.39  0.78  0.2   0.78  0.1                        P. aeruginosa A5007                                                                          0.2   0.39  0.39  0.78  0.39  0.78  0.1                        P. aeruginosa K799/WT                                                                        0.2   0.39  0.39  0.78  0.39  0.78  0.1                        P. aeruginosa K799/61                                                                        0.05  0.05  0.2   0.1   0.05  0.2   0.02                       Pseudomonas cepacia 296I                                                                     3.1   1.56  1.56  1.56  1.56  6.2   3.1                        Acinetob. calcoaceticus CMX 669                                                              0.02  0.005 0.05  0.1   0.05  0.39  0.78                       P. aeruginosa 5263                                                                           3.1   12.5  6.2   100   50    25    12.5                       P. aeruginosa 2862                                                                           3.2   12.5  12.5  50    12.5  25    12.5                       Candida albicans CCH 442                                                                     >100  50    >100  >100  >100  >100  >100                       Myco. smegmatis ATCC 114                                                                     0.02  0.01  0.1   0.2   0.05  0.78  0.78                       Nocardia asteroides ATCC 9970                                                                0.2   0.2   0.78  25    0.78  50    25                         __________________________________________________________________________    Organisms      Ex. 327                                                                              Ex. 328                                                                              Ex. 329                                                                              Ex. 330                                                                              Ex. 331                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.1    0.78   0.78   0.1    0.1    0.2                         Staph. aureus A5177                                                                          0.2    3.1    1.56   0.39   0.1    0.39                        Staph. aureus 5278                                                                           0.2    3.1    1.56   0.39   0.1    0.39                        Staph. aureus 642A                                                                           0.39   3.1    1.56   0.2    0.1    0.39                        Staph. aureus NCTC 10649                                                                     0.1    0.78   1.56   0.2    0.1    0.39                        Staph. aureus CMX 553                                                                        0.39   6.2    1.56   0.39   0.2    0.78                        Staph. aureus 1775 Cipro. R.                                                                 25     >100   50     6.2    12.5   >100                        Staph. epidermidis 3519                                                                      0.2    1.56   1.56   0.2    0.1    0.39                        Entero. faecium ATCC 8043                                                                    0.39   3.1    6.2    0.39   0.2    0.39                        Strep. bovis A5169                                                                           0.2    1.56   6.2           0.78   1.56                        Strep. agalactiae CMX 508                                                                    0.2    1.56   3.1    1.56   0.39   0.39                        Strep. pyogenes EES61                                                                        0.2    1.56   3.1    1.56   0.39   0.78                        Strep. pyogenes 930 CONST                                                                    0.2    1.56   3.1    0.78   0.2    0.78                        Strep. pyogenes 2548 INDUC                                                                   0.2    1.56   1.56   0.78   0.2    0.39                        M. luteus ATCC 9341                                                                          0.78   12.5   25     1.56   0.78   1.56                        M. luteus ATCC 4698                                                                          0.78   12.5   6.2    1.56   0.78   0.78                        Escherichia coli Juhl                                                                        0.1    0.39   0.2    0.39   0.01   0.01                        E. coli SS     0.0005 0.02   0.01   0.02   0.002  0.005                       E. coli DC-2   0.78   12.5   3.1    3.1    0.2    0.2                         E. coli H560   0.1    0.78   0.1    0.78   0.02   0.01                        E. coli KNK 437                                                                              0.78   6.2    3.1    3.1    0.2    0.2                         Enter. aerogenes ATCC 13048                                                                  0.78   3.1    0.39   0.39   0.05   0.02                        Klebs. pneumoniae ATCC 8045                                                                  0.39   1.56   0.1    0.2    0.02   0.02                        Providencia stuartii CMX 640                                                                 12.5   50     12.5   12.5   0.78   0.78                        P. aeruginosa BMH 10                                                                         1.56   12.5   1.56   6.2    0.1    0.1                         P. aeruginosa A5007                                                                          1.56   12.5   1.56   6.2    0.2    0.1                         P. aeruginosa K799/WT                                                                        1.56   12.5   1.56   6.2    0.2    0.1                         P. aeruginosa K799/61                                                                        0.2    1.56   0.39   0.2    0.05   0.02                        Pseudomonas cepacia 296I                                                                     25     >100   25     3.1    1.56   3.1                         Acinetob. calcoaceticus CMX 669                                                              1.56   6.2    0.78   3.1    0.2    0.78                        P. aeruginosa 5263                                                                           50     >100   100    >100   12.5   12.5                        P. aeruginosa 2862                                                                           50     >100   100    >100   12.5   12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     1.56   1.56   1.56   25     0.1    0.78                        Nocardia asteroides ATCC 9970                                                                50     >100   50     >100   12.5   25                          __________________________________________________________________________    Organisms      Ex. 332                                                                              Ex. 333                                                                              Ex. 334                                                                              Ex. 335                                                                              Ex. 336                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.1    0.01   0.02   0.78   0.005  0.2                         Staph. aureus A5177                                                                          0.2    0.01   0.02   1.56   0.005  0.39                        Staph. aureus 5278                                                                           0.2    0.01   0.02   3.1    0.01   0.39                        Staph. aureus 642A                                                                           0.2    0.01   0.02   1.56   0.01   0.39                        Staph. aureus NCTC 10649                                                                     0.1    0.01   0.02   1.56   0.005  0.39                        Staph. aureus CMX 553                                                                        0.39   0.02   0.02   3.1    0.02   0.78                        Staph. aureus 1775 Cipro. R.                                                                 6.2    0.78   0.78   >100   0.39   >100                        Staph. epidermidis 3519                                                                      0.2    0.01   0.02   1.56   0.01   0.39                        Entero. faecium ATCC 8043                                                                    0.39   0.05   0.05   3.1    0.02   0.39                        Strep. bovis A5169    0.2    0.02   12.5   0.01   1.56                        Strep. agalactiae CMX 508                                                                    0.39   0.05   0.05   6.2    0.01   0.39                        Strep. pyogenes EES61                                                                        0.39   0.05   0.05   6.2    0.01   0.78                        Strep. pyogenes 930 CONST                                                                    0.39   0.05   0.02   6.2    0.01   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.39   0.05   0.01   3.1    0.005  0.39                        M. luteus ATCC 9341                                                                          0.78   0.1    0.05   3.1    0.05   1.56                        M. luteus ATCC 4698                                                                          3.1    0.05   0.05   6.2    0.05   0.78                        Escherichia coli Juhl                                                                        0.2    0.01   0.005  0.2    0.02   0.01                        E. coli SS     0.02   0.001  0.001  0.02   0.001  0.005                       E. coli DC-2   1.56   0.1    0.05   1.56   0.1    0.2                         E. coli H560   0.2    0.05   0.01   0.2    0.01   0.01                        E. coli KNK 437                                                                              1.56   0.1    0.05   1.56   0.1    0.2                         Enter. aerogenes ATCC 13048                                                                  0.39   0.2    0.02   0.39   0.1    0.02                        Klebs. pneumoniae ATCC 8045                                                                  0.1    0.05   0.005  0.2    0.02   0.02                        Providencia stuartii CMX 640                                                                 3.1    0.39   0.78   6.2    0.78   0.78                        P. aeruginosa BMH 10                                                                         1.56   0.78   0.1    0.39   0.39   0.1                         P. aeruginosa A5007                                                                          1.56   0.39   0.1    0.78   0.39   0.1                         P. aeruginosa K799/WT                                                                        1.56   0.39   0.1    0.78   0.39   0.1                         P. aeruginosa K799/61                                                                        0.39   0.05   0.05   0.2    0.05   0.02                        Pseudomonas cepacia 296I                                                                     6.2    1.56   0.39   6.2    6.2    3.1                         Acinetob. calcoaceticus CMX 669                                                              0.39   0.2    0.01   3.1    0.05   0.78                        P. aeruginosa 5263                                                                           100    12.5   3.1    25     6.2    12.5                        P. aeruginosa 2862                                                                           50     12.5   1.56   50     12.5   12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     50     0.39   1.56   25     0.02   0.78                        Nocardia asteroides ATCC 9970                                                                50     12.5   1.56   100    0.78   25                          __________________________________________________________________________    Organisms      Ex. 337                                                                              Ex. 338                                                                              Ex. 339                                                                              Ex. 340                                                                              Ex. 341                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.005  0.02   0.1    0.01   0.005  0.2                         Staph. aureus A5177                                                                          0.01   0.05   0.2    0.02   0.005  0.39                        Staph. aureus 5278                                                                           0.01   0.02   0.2    0.02   0.005  0.39                        Staph. aureus 642A                                                                           0.01   0.05   0.2    0.05   0.01   0.39                        Staph. aureus NCTC 10649                                                                     0.005  0.02   0.2    0.02   0.005  0.39                        Staph. aureus CMX 553                                                                        0.01   0.05   0.39   0.02   0.02   0.78                        Staph. aureus 1775 Cipro. R.                                                                 0.2    0.78   6.2    0.2    0.39   >100                        Staph. epidermidis 3519                                                                      0.01   0.05   0.2    0.02   0.01   0.39                        Entero. faecium ATCC 8043                                                                    0.01   0.1    0.2    0.05   0.02   0.39                        Strep. bovis A5169                                                                           0.002  0.05   0.39   0.05   0.01   1.56                        Strep. agalactiae CMX 508                                                                    0.005  0.05   0.2    0.02   0.01   0.39                        Strep. pyogenes EES61                                                                        0.002  0.05   0.2    0.05   0.02   0.78                        Strep. pyogenes 930 CONST                                                                    0.002  0.05   0.2    0.05   0.02   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.002  0.05   0.2    0.05   0.01   0.39                        M. luteus ATCC 9341                                                                          0.05   0.2    0.39   0.2    0.05   1.56                        M. luteus ATCC 4698                                                                          0.01   0.1    0.2    0.05   0.05   0.78                        Escherichia coli Juhl                                                                        0.005  0.02   0.02   0.05   0.02   0.01                        E. coli SS     0.0005 0.002  0.002  0.005  0.0005 0.005                       E. coli DC-2   0.05   0.39   0.2    0.78   0.2    0.2                         E. coli H560   0.002  0.02   0.05   0.02   0.02   0.01                        E. coli KNK 437                                                                              0.1    0.2    0.2    0.78   0.1    0.2                         Enter. aerogenes ATCC 13048                                                                  0.01   0.1    0.1    0.78   0.1    0.02                        Klebs. pneumoniae ATCC 8045                                                                  0.005  0.05   0.05   0.05   0.02   0.02                        Providencia stuartii CMX 640                                                                 0.39   3.1    0.78   1.56   0.78   0.78                        P. aeruginosa BMH 10                                                                         0.1    0.78   0.2    1.56   0.2    0.1                         P. aeruginosa A5007                                                                          0.2    0.78   0.2    0.78   0.39   0.1                         P. aeruginosa K799/WT                                                                        0.2    0.78   0.2    0.78   0.39   0.1                         P. aeruginosa K799/61                                                                        0.05   0.1    0.05   0.05   0.05   0.02                        Pseudomonas cepacia 296I                                                                     3.1    3.1    3.1    0.78   0.78   3.1                         Acinetob. calcoaceticus CMX 669                                                              0.02   0.1    0.39   0.2    0.05   0.78                        P. aeruginosa 5263                                                                           3.1    25     6.2    12.5   3.1    12.5                        P. aeruginosa 2862                                                                           6.2    25     6.2    12.5   6.2    12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.01   0.1    0.2    0.78   0.1    0.78                        Nocardia asteroides ATCC 9970                                                                0.39   1.56   6.2    6.2    0.78   25                          __________________________________________________________________________    Organisms      Ex. 342                                                                              Ex. 343                                                                              Ex. 344                                                                              Ex. 345                                                                              Ex. 346                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.005  0.02   0.02   0.1    3.1    0.2                         Staph. aureus A5177                                                                          0.005  0.05   0.05   0.2    6.2    0.39                        Staph. aureus 5278                                                                           0.005  0.05   0.05   0.2    6.2    0.39                        Staph. aureus 642A                                                                           0.01   0.05   0.05   0.2    12.5   0.39                        Staph. aureus NCTC 10649                                                                     0.005  0.02   0.02   0.2    3.1    0.39                        Staph. aureus CMX 553                                                                        0.01   0.05   0.05   0.39   12.5   0.78                        Staph. aureus 1775 Cipro. R.                                                                 0.1    1.56   0.78   25     >100   >100                        Staph. epidermidis 3519                                                                      0.005  0.05   0.05   0.2    12.5   0.39                        Entero. faecium ATCC 8043                                                                    0.02   0.1    0.1    0.2    100    0.39                        Strep. bovis A5169                                                                           0.002  0.1    0.2    0.78   50     1.56                        Strep. agalactiae CMX 508                                                                    0.002  0.05   0.2    0.39   25     0.39                        Strep. pyogenes EES61                                                                        0.005  0.1    0.2    0.39   25     0.78                        Strep. pyogenes 930 CONST                                                                    0.01   0.1    0.2    0.2    25     0.78                        Strep. pyogenes 2548 INDUC                                                                   0.005  0.1    0.2    0.2    25     0.39                        M. luteus ATCC 9341                                                                          0.05   0.1    0.2    0.39   50     1.56                        M. luteus ATCC 4698                                                                          0.02   0.05   0.1    0.2    25     0.78                        Escherichia coli Juhl                                                                        0.01   0.01   0.02   0.02   3.1    0.01                        E. coli SS     0.0005 0.002  0.002  0.002  0.1    0.005                       E. coli DC-2   0.1    0.1    0.39   0.39   50     0.2                         E. coli H560   0.01   0.01   0.2    0.05   6.2    0.01                        E. coli KNK 437                                                                              0.2    0.1    0.2    0.39   12.5   0.2                         Enter. aerogenes ATCC 13048                                                                  0.1    0.02   0.05   0.1    12.5   0.02                        Klebs. pneumoniae ATCC 8045                                                                  0.02   0.01   0.02   0.05   1.56   0.02                        Providencia stuartii CMX 640                                                                 0.39   0.78   1.56   3.1    >100   0.78                        P. aeruginosa BMH 10                                                                         0.2    0.2    0.39   0.39   25     0.1                         P. aeruginosa A5007                                                                          0.39   0.2    0.78   0.78   25     0.1                         P. aeruginosa K799/WT                                                                        0.39   0.2    0.78   0.78   25     0.1                         P. aeruginosa K799/61                                                                        0.05   0.02   0.05   0.1    1.56   0.02                        Pseudomonas cepacia 296I                                                                     1.56   1.56   0.78   3.1    >100   3.1                         Acinetob. calcoaceticus CMX 669                                                              0.05   0.02   0.05   0.2    6.2    0.78                        P. aeruginosa 5263                                                                           3.1    3.1    12.5   12.5   >100   12.5                        P. aeruginosa 2862                                                                           6.2    6.2    12.5   6.2    >100   12.5                        Candida albicans CCH 442                                                                     50     >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.1    0.1    0.1    3.1    6.2    0.78                        Nocardia asteroides ATCC 9970                                                                0.39   12.5   12.5   25     100    25                          __________________________________________________________________________    Organisms      Ex. 348                                                                              Ex. 349                                                                              Ex. 350                                                                              Ex. 351                                                                              Ex. 352                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.01   0.05   0.02   0.05   0.05   0.2                         Staph. aureus A5177                                                                          0.02   0.1    0.05   0.1    0.05   0.39                        Staph. aureus 5278                                                                           0.01   0.1    0.05   0.1    0.05   0.39                        Staph. aureus 642A                                                                           0.02   0.1    0.05   0.1    0.05   0.39                        Staph. aureus NCTC 10649                                                                     0.01   0.05   0.05   0.05   0.05   0.39                        Staph. aureus CMX 553                                                                        0.02   0.1    0.05   0.1    0.05   0.78                        Staph. aureus 1775 Cipro. R.                                                                 0.39   3.1    3.1    3.1    0.78   >100                        Staph. epidermidis 3519                                                                      0.02   0.1    0.05   0.1    0.05   0.39                        Entero. faecium ATCC 8043                                                                    0.1    0.39   0.1    0.39   0.39   0.39                        Strep. bovis A5169                                                                           0.1    0.39   0.1    0.39   0.39   1.56                        Strep. agalactiae CMX 508                                                                    0.1    0.39   0.05   0.39   0.39   0.39                        Strep. pyogenes EES61                                                                        0.1    0.39   0.1    0.39   0.39   0.78                        Strep. pyogenes 930 CONST                                                                    0.1    0.2    0.05   0.39   0.39   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.1    0.2    0.05   0.39   0.2    0.39                        M. luteus ATCC 9341                                                                          0.2    0.39   0.05   0.2    0.39   1.56                        M. luteus ATCC 4698                                                                          0.1    0.39   0.05   0.2    0.2    0.78                        Escherichia coli Juhl                                                                        0.2    0.05   0.01   0.1    0.78   0.01                        E. coli SS     0.01   0.005  0.005  0.005  0.02   0.005                       E. coli DC-2   1.56   0.78   0.1    0.78   6.2    0.2                         E. coli H560   0.2    0.1    0.01   0.1    0.39   0.01                        E. coli KNK 437                                                                              0.78   0.39   0.1    0.78   3.1    0.2                         Enter. aerogenes ATCC 13048                                                                  0.78   0.2    0.1    0.2    1.56   0.02                        Klebs. pneumoniae ATCC 8045                                                                  0.39   0.05   0.01   0.05   0.78   0.02                        Providencia stuartii CMX 640                                                                 3.1    3.1    1.56   3.1    6.2    0.78                        P. aeruginosa BMH 10                                                                         3.1    0.78   0.1    1.56   6.2    0.1                         P. aeruginosa A5007                                                                          3.1    1.56   0.2    1.56   6.2    0.1                         P. aeruginosa K799/WT                                                                        1.56   1.56   0.2    1.56   3.1    0.1                         P. aeruginosa K799/61                                                                        0.2    0.2    0.05   0.2    0.39   0.02                        Pseudomonas cepacia 296I                                                                     6.2    3.1    3.1    3.1    6.2    3.1                         Acinetob. calcoaceticus CMX 669                                                              0.39   0.1    0.05   0.39   0.78   0.78                        P. aeruginosa 5263                                                                           50     25     3.1    50     >100   12.5                        P. aeruginosa 2862                                                                           25     25     3.1    25     100    12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.39   0.2    0.05   0.2    0.78   0.78                        Nocardia asteroides ATCC 9970                                                                3.1    12.5   3.1    25     25     25                          __________________________________________________________________________    Organisms      Ex. 353                                                                              Ex. 354                                                                              Ex. 355                                                                              Ex. 356                                                                              357    Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.1    0.01   0.02   0.02   0.02   0.2                         Staph. aureus A5177                                                                          0.2    0.05   0.02   0.05   0.05   0.39                        Staph. aureus 5278                                                                           0.2    0.05   0.02   0.05   0.05   0.39                        Staph. aureus 642A                                                                           0.2    0.05   0.05   0.05   0.05   0.39                        Staph. aureus NCTC 10649                                                                     0.1    0.02   0.02   0.05   0.05   0.39                        Staph. aureus CMX 553                                                                        0.2    0.05   0.05   0.1    0.1    0.78                        Staph. aureus 1775 Cipro. R.                                                                 6.2    0.39   3.1    1.56   3.1    >100                        Staph. epidermidis 3519                                                                      0.2    0.05   0.05   0.05   0.05   0.39                        Entero. faecium ATCC 8043                                                                    0.39   0.1    0.05   0.1    0.2    0.39                        Strep. bovis A5169                                                                           0.39   na     0.05   0.1    0.2    1.56                        Strep. agalactiae CMX 508                                                                    0.39   0.1    0.05   0.1    0.1    0.39                        Strep. pyogenes EES61                                                                        0.39   0.1    0.05   0.1    0.2    0.78                        Strep. pyogenes 930 CONST                                                                    0.39   0.2    0.05   0.1    0.2    0.78                        Strep. pyogenes 2548 INDUC                                                                   0.2    0.2    0.05   0.05   0.2    0.39                        M. luteus ATCC 9341                                                                          0.39   0.39   0.1    0.1    0.2    1.56                        M. luteus ATCC 4698                                                                          0.39   0.2    0.1    0.1    0.2    0.78                        Escherichia coli Juhl                                                                        0.05   0.78   0.02   0.01   0.1    0.01                        E. coli SS     0.001  0.02   0.005  0.001  0.001  0.005                       E. coli DC-2   0.39   3.1    0.2    0.2    0.78   0.2                         E. coli H560   0.1    0.78   0.05   0.01   0.1    0.01                        E. coli KNK 437                                                                              0.78   3.1    0.2    0.1    0.78   0.2                         Enter. aerogenes ATCC 13048                                                                  0.2    3.1    0.1    0.05   0.39   0.02                        Klebs. pneumoniae ATCC 8045                                                                  0.05   0.78   0.05   0.01   0.1    0.02                        Providencia stuartii CMX 640                                                                 3.1    6.2    1.56   0.78   6.2    0.78                        P. aeruginosa BMH 10                                                                         0.39   6.2    0.39   0.2    1.56   0.1                         P. aeruginosa A5007                                                                          1.56   6.2    0.39   0.2    1.56   0.1                         P. aeruginosa K799/WT                                                                        1.56   6.2    0.39   0.2    6.2    0.1                         P. aeruginosa K799/61                                                                        0.1    0.39   0.05   0.02   0.2    0.02                        Pseudomonas cepacia 296I                                                                     3.1    25     1.56   1.56   6.2    3.1                         Acinetob. calcoaceticus CMX 669                                                              0.2    1.56   0.1    0.05   0.2    0.78                        P. aeruginosa 5263                                                                           25     >100   6.2    3.1    50     12.5                        P. aeruginosa 2862                                                                           25     >100   12.5   6.2    50     12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.2    6.2    0.78   0.1    0.1    0.78                        Nocardia asteroides ATCC 9970                                                                12.5   >100   12.5   3.1    6.2    25                          __________________________________________________________________________    Organisms      Ex. 358                                                                              Ex. 359                                                                              Ex. 360                                                                              Ex. 361                                                                              Ex. 362                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.1    0.1    0.02   0.01   0.02   0.2                         Staph. aureus A5177                                                                          0.2    0.1    0.2    0.02   0.05   0.39                        Staph. aureus 5278                                                                           0.2    0.1    0.2    0.02   0.1    0.39                        Staph. aureus 642A                                                                           0.2    0.1    0.2    0.02   0.05   0.39                        Staph. aureus NCTC 10649                                                                     0.2    0.1    0.1    0.02   0.05   0.39                        Staph. aureus CMX 553                                                                        0.39   0.2    0.39   0.05   0.1    0.78                        Staph. aureus 1775 Cipro. R.                                                                 25     6.2    12.5   1.56   12.5   >100                        Staph. epidermidis 3519                                                                      0.2    0.1    0.2    0.02   0.05   0.39                        Entero. faecium ATCC 8043                                                                    0.2    0.2    0.1    0.05   0.05   0.39                        Strep. bovis A5169                                                                           0.2    0.2    0.02   0.02   0.1    1.56                        Strep. agalactiae CMX 508                                                                    0.2    0.1    0.01   0.01   0.05   0.39                        Strep. pyogenes EES61                                                                        0.2    0.1    0.02   0.01   0.1    0.78                        Strep. pyogenes 930 CONST                                                                    0.2    0.2    0.02   0.01   0.05   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.2    0.2    0.02   0.01   0.05   0.39                        M. luteus ATCC 9341                                                                          0.2    0.39   0.39   0.05   0.2    1.56                        M. luteus ATCC 4698                                                                          0.2    0.39   0.39   0.05   0.1    0.78                        Escherichia coli Juhl                                                                        0.1    0.1    0.1    0.02   0.1    0.01                        E. coli SS     0.005  0.002  0.005  0.002  0.005  0.005                       E. coli DC-2   0.78   0.78   0.78   0.2    0.78   0.2                         E. coli H560   0.2    0.1    0.2    0.05   0.1    0.01                        E. coli KNK 437                                                                              0.78   0.78   0.78   0.39   0.78   0.2                         Enter. aerogenes ATCC 13048                                                                  0.39   0.78   0.39   0.1    0.2    0.02                        Klebs. pneumoniae ATCC 8045                                                                  0.1    0.1    0.2    0.02   0.05   0.02                        Providencia stuartii CMX 640                                                                 3.1    12.5   6.2    3.1    6.2    0.78                        P. aeruginosa BMH 10                                                                         0.39   1.56   0.39   0.2    0.39   0.1                         P. aeruginosa A5007                                                                          0.39   3.1    0.78   0.78   0.78   0.1                         P. aeruginosa K799/WT                                                                        0.78   1.56   0.39   0.78   0.78   0.1                         P. aeruginosa K799/61                                                                        0.05   0.39   0.1    0.1    0.05   0.02                        Pseudomonas cepacia 296I                                                                     12.5   12.5   12.5   3.1    6.2    3.1                         Acinetob. calcoaceticus CMX 669                                                              3.1    0.78   3.1    0.1    0.78   0.78                        P. aeruginosa 5263                                                                           6.2    50     6.2    6.2    25     12.5                        P. aeruginosa 2862                                                                           12.5   100    12.5   6.2    25     12.5                        Candida albicans CCH 442                                                                     100    >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.2    0.39   0.78   1.56   0.05   0.78                        Nocardia asteroides ATCC 9970                                                                6.2    25     25     0.78   3.1    25                          __________________________________________________________________________    Organisms      Ex. 363                                                                              Ex. 364                                                                              Ex. 365                                                                              Ex. 366                                                                              Ex. 367                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.01   0.05   0.01   0.1    0.05   0.2                         Staph. aureus A5177                                                                          0.02   0.1    0.02   0.1    0.1    0.39                        Staph. aureus 5278                                                                           0.02   0.1    0.02   0.1    0.1    0.39                        Staph. aureus 642A                                                                           0.02   0.2    0.05   0.1    0.1    0.39                        Staph. aureus NCTC 10649                                                                     0.01   0.05   0.01   0.05   0.05   0.39                        Staph. aureus CMX 553                                                                        0.05   0.2    0.05   0.1    0.2    0.78                        Staph. aureus 1775 Cipro. R.                                                                 1.56   3.1    1.56   1.56   3.1    >100                        Staph. epidermidis 3519                                                                      0.05   0.1    0.02   0.1    0.1    0.39                        Entero. faecium ATCC 8043                                                                    0.05   0.39   0.05   0.2    0.39   0.39                        Strep. bovis A5169                                                                           0.05   0.78   0.05   0.2    0.39   1.56                        Strep. agalactiae CMX 508                                                                    0.05   0.39   0.02   0.05   0.39   0.39                        Strep. pyogenes EES61                                                                        0.05   0.39   0.02   0.2    0.39   0.78                        Strep. pyogenes 930 CONST                                                                    0.05   0.39   0.05   0.2    0.39   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.02   0.39   0.02   0.2    0.39   0.39                        M. luteus ATCC 9341                                                                          0.1    0.39   0.1    0.39   0.39   1.56                        M. luteus ATCC 4698                                                                          0.1    0.2    0.1    0.2    0.39   0.78                        Escherichia coli Juhl                                                                        0.05   0.78   0.02   0.05   0.39   0.01                        E. coli SS     0.01   0.05   0.002  0.05   0.01   0.005                       E. coli DC-2   0.78   12.5   0.1    0.39   1.56   0.2                         E. coli H560   0.1    1.56   0.02   0.05   0.39   0.01                        E. coli KNK 437                                                                              0.39   6.2    0.2    0.39   3.1    0.2                         Enter. aerogenes ATCC 13048                                                                  0.39   3.1    0.05   0.2    0.78   0.02                        Klebs. pneumoniae ATCC 8045                                                                  0.1    1.56   0.1    0.05   0.39   0.02                        Providencia stuartii CMX 640                                                                 3.1    12.5   0.78   3.1    12.5   0.78                        P. aeruginosa BMH 10                                                                         0.39   12.5   0.2    0.78   3.1    0.1                         P. aeruginosa A5007                                                                          1.56   12.5   0.39   0.78   6.2    0.1                         P. aeruginosa K799/WT                                                                        1.56   12.5   0.39   0.78   3.1    0.1                         P. aeruginosa K799/61                                                                        0.39   0.78   0.05   0.2    0.1    0.02                        Pseudomonas cepacia 296I                                                                     3.1    12.5   1.56   3.1    6.2    3.1                         Acinetob. calcoaceticus CMX 669                                                              0.2    1.56   0.1    0.1    0.78   0.78                        P. aeruginosa 5263                                                                           12.5   >100   6.2    12.5   100    12.5                        P. aeruginosa 2862                                                                           25     >100   6.2    25     >100   12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.39   3.1    0.1    0.78   6.2    0.78                        Nocardia asteroides ATCC 9970                                                                12.5   12.5   1.56   12.5   50     25                          __________________________________________________________________________    Organisms      Ex. 368                                                                              Ex. 369                                                                              Ex. 370                                                                              Ex. 371                                                                              Ex. 372                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.005  0.01   0.02   0.005  0.05   0.2                         Staph. aureus A5177                                                                          0.01   0.02   0.05   0.01   0.05   0.39                        Staph. aureus 5278                                                                           0.01   0.02   0.05   0.01   0.05   0.39                        Staph. aureus 642A                                                                           0.01   0.05   0.1    0.01   0.1    0.39                        Staph. aureus NCTC 10649                                                                     0.005  0.01   0.05   0.005  0.05   0.39                        Staph. aureus CMX 553                                                                        0.01   0.05   0.1    0.01   0.1    0.78                        Staph. aureus 1775 Cipro. R.                                                                 0.1    0.2    1.56   0.39   0.78   >100                        Staph. epidermidis 3519                                                                      0.01   0.02   0.05   0.01   0.05   0.39                        Entero. faecium ATCC 8043                                                                    0.01   0.1    0.1    0.02   0.39   0.39                        Strep. bovis A5169                                                                           0.01   0.2    0.1    0.002  0.1    1.56                        Strep. agalactiae CMX 508                                                                    0.002  0.1    0.1    0.002  0.05   0.39                        Strep. pyogenes EES61                                                                        0.01   0.1    0.1    0.005  0.1    0.78                        Strep. pyogenes 930 CONST                                                                    0.01   0.1    0.1    0.01   0.2    0.78                        Strep. pyogenes 2548 INDUC                                                                   0.005  0.1    0.05   0.01   0.1    0.39                        M. luteus ATCC 9341                                                                          0.02   0.2    0.2    0.02   0.78   1.56                        M. luteus ATCC 4698                                                                          0.05   0.05   0.1    0.02   0.78   0.78                        Escherichia coli Juhl                                                                        0.02   0.2    0.05   0.02   0.78   0.01                        E. coli SS     0.002  0.01   0.002  0.002  0.01   0.005                       E. coli DC-2   0.1    1.56   0.39   0.1    1.56   0.2                         E. coli H560   0.01   0.2    0.05   0.01   0.39   0.01                        E. coli KNK 437                                                                              0.1    1.56   0.39   0.2    3.1    0.2                         Enter. aerogenes ATCC 13048                                                                  0.05   0.39   0.2    0.05   3.1    0.02                        Klebs. pneumoniae ATCC 8045                                                                  0.01   0.05   0.1    0.02   0.78   0.02                        Providencia stuartii CMX 640                                                                 0.78   3.1    3.1    0.78   12.5   0.78                        P. aeruginosa BMH 10                                                                         0.2    1.56   0.78   0.2    3.1    0.1                         P. aeruginosa A5007                                                                          0.39   1.56   0.78   0.39   12.5   0.1                         P. aeruginosa K799/WT                                                                        0.39   1.56   0.78   0.39   12.5   0.1                         P. aeruginosa K799/61                                                                        0.05   0.05   0.1    0.05   0.78   0.02                        Pseudomonas cepacia 296I                                                                     1.56   0.78   6.2    1.56   25     3.1                         Acinetob. calcoaceticus CMX 669                                                              0.01   0.1    0.05   0.05   0.78   0.78                        P. aeruginosa 5263                                                                           3.1    12.5   12.5   6.2    >100   12.5                        P. aeruginosa 2862                                                                           6.2    50     25     6.2    >100   12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   100    >100                        Myco. smegmatis ATCC 114                                                                     0.01   0.2    0.2    0.02   3.1    0.78                        Nocardia asteroides ATCC 9970                                                                0.78   12.5   12.5   0.2    25     25                          __________________________________________________________________________    Organisms           Ex. 373  Ex. 374  Ex. 413 Cntl                            __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                          0.05     0.02     0.002   0.2                             Staph. aureus A5177 0.1      0.02     0.005   0.39                            Staph. aureus 5278  0.1      0.02     0.005   0.39                            Staph. aureus 642A  0.2      0.05     0.005   0.39                            Staph. aureus NCTC 10649                                                                          0.1      0.02     0.002   0.39                            Staph. aureus CMX 553                                                                             0.39     0.1      0.01    0.78                            Staph. aureus 1775 Cipro. R.                                                                      6.2      0.78     0.05    >100                            Staph. epidermidis 3519                                                                           0.1      0.05     0.005   0.39                            Entero. faecium ATCC 8043                                                                         0.2      0.1      0.005   0.39                            Strep. bovis A5169  0.1      0.1      0.002   1.56                            Strep. agalactiae CMX 508                                                                         0.1      0.1      0.001   0.39                            Strep. pyogenes EES61                                                                             0.1      0.1      0.002   0.78                            Strep. pyogenes 930 CONST                                                                         0.2      0.1      0.002   0.78                            Strep. pyogenes 2548 INDUC                                                                        0.1      0.1      0.002   0.39                            M. luteus ATCC 9341 0.39     0.2      0.02    1.56                            M. luteus ATCC 4698 0.39     0.2      0.02    0.78                            Escherichia coli Juhl                                                                             0.39     0.2      0.02    0.01                            E. coli SS          0.01     0.005    0.002   0.005                           E. coli DC-2        1.56     0.78     0.05    0.2                             E. coli H560        0.2      0.39     0.01    0.01                            E. coli KNK 437     1.56     0.05     0.1     0.2                             Enter. aerogenes ATCC 13048                                                                       0.78     6.2      0.02    0.02                            Klebs. pneumoniae ATCC 8045                                                                       0.39     1.56     0.01    0.02                            Providencia stuartii CMX 640                                                                      12.5     1.56     0.78    0.78                            P. aeruginosa BMH 10                                                                              3.1      3.1      0.2     0.1                             P. aeruginosa A5007 3.1      0.39     0.39    0.1                             P. aeruginosa K799/WT                                                                             3.1      6.2      0.39    0.1                             P. aeruginosa K799/61                                                                             0.78     0.39     0.05    0.02                            Pseudomonas cepacia 296I                                                                          12.5     6.2      1.56    3.1                             Acinetob. calcoaceticus CMX 669                                                                   0.78     0.2      0.02    0.78                            P. aeruginosa 5263  50       100      6.2     12.5                            P. aeruginosa 2862  100      50       12.5    12.5                            Candida albicans CCH 442                                                                          >100     >100     100     >100                            Myco. smegmatis ATCC 114                                                                          1.56     0.2      0.2     0.78                            Nocardia asteroides ATCC 9970                                                                     25       1.56     0.2     25                              __________________________________________________________________________    Organisms      Ex. 414                                                                              Ex. 415                                                                              Ex. 416                                                                              Ex. 417                                                                              Ex. 418                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.01   0.01   0.01   0.1    0.01   0.05                        Staph. aureus A5177                                                                          0.05   0.05   0.02   0.2    0.01   0.39                        Staph. aureus 5278                                                                           0.05   0.05   0.01   0.1    0.002  0.39                        Staph. aureus 642A                                                                           0.05   0.05   0.02   0.1    0.01   0.39                        Staph. aureus NCTC 10649M                                                                    0.05   0.02   0.01   0.1    0.01   0.39                        Staph. aureus CMX 553                                                                        0.1    0.1    0.02   --     0.002  0.78                        Staph. aureus 1775 Cipro. R.                                                                 6.2    6.2    0.78   0.39   0.78   >100                        Staph. epidermidis 3519                                                                      0.05   0.05   0.02   --     0.01   0.39                        Entero. faecium ATCC 8043                                                                    0.02   0.2    0.1    0.1    0.05   0.78                        Strep. bovis A5169                                                                           0.2    0.2    0.1    0.2    0.05   1.56                        Strep. agalactiae CMX 508                                                                    0.2    0.1    0.1    0.05   0.05   0.78                        Strep. pyogenes EES61                                                                        0.1    0.1    0.1    0.1    0.1    0.39                        Strep. pyogenes 930 CONST                                                                    0.1    0.2    0.1    0.1    0.05   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.1    0.1    0.1    0.05   0.05   0.39                        M. luteus ATCC 9341                                                                          0.2    0.39   0.2    0.2    0.1    3.1                         M. luteus ATCC 4698                                                                          0.1    0.1    0.1    0.2    0.05   1.56                        Escherichia coli Juhl                                                                        0.1    0.39   0.1    0.2    0.1    0.05                        E. coli SS     0.005  0.005  0.005  0.2    0.005  0.005                       E. coli DC-2   1.56   3.1    0.78   1.56   1.56   0.2                         E. coli H560   0.2    0.39   0.2    0.39   0.1    0.01                        E. coli KNK 437                                                                              0.78   1.56   0.78   0.78   0.78   0.2                         Enter. aerogenes ATCC 13048                                                                  0.39   0.78   0.39   0.39   0.2    0.05                        Klebs. pneunoniae ATCC 8045                                                                  0.05   0.1    0.1    0.1    0.78   0.01                        Providencia stuartii CMX 640                                                                 3.1    6.2    1.56   3.1    1.56   0.78                        P. aeruginosa BMH 10                                                                         1.56   3.1    0.78   1.56   1.56   0.1                         P. aeruginosa A5007                                                                          1.56   3.1    1.56   1.56   0.78   0.2                         P. aeruginosa K799/WT                                                                        1.56   3.1    1.56   6.2    0.78   0.1                         P. aeruginosa K799/61                                                                        0.1    0.2    0.1    0.2    0.1    0.02                        Pseudomonas cepacia 296I                                                                     3.1    6.2    0.78   1.56   0.78   3.1                         Acinetob. calcoaceticus CMX 669                                                              0.39   0.78   0.2    0.39   0.1    0.39                        P. aeruginosa 5263                                                                           25     50     25     25     25     12.5                        P. aeruginosa 2862                                                                           50     50     25     25     25     12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.1    0.2    0.39   0.39   --     1.56                        Nocardia asteroides ATCC 9970                                                                6.2    12.5   6.2    6.2    --     25                          __________________________________________________________________________    Organisms      Ex. 419                                                                              Ex. 420                                                                              Ex. 421                                                                              Ex. 422                                                                              Ex. 423                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.39   0.01   0.05   0.005  0.01   0.05                        Staph. aureus A5177                                                                          0.78   0.02   0.05   0.01   0.02   0.39                        Staph. aureus 5278                                                                           0.78   0.01   0.05   0.005  0.02   0.39                        Staph. aureus 642A                                                                           0.78   0.02   0.05   0.01   0.02   0.39                        Staph. aureus NCTC 10649M                                                                    0.39   0.01   0.05   0.005  0.02   0.39                        Staph. aureus CMX 553                                                                        0.78   0.05   0.05   0.01   0.05   0.78                        Staph. aureus 1775 Cipro. R.                                                                 100    0.39   0.78   0.39   0.78   >100                        Staph. epidermidis 3519                                                                      0.78   0.02   0.05   0.01   0.02   0.39                        Entero. faecium ATCC 8043                                                                    3.1    0.1    0.05   0.05   0.1    0.78                        Strep. bovis A5169                                                                           --     0.05   0.1    0.05   0.2    1.56                        Strep. agalactiae CMX 508                                                                    3.1    0.05   0.05   0.02   0.1    0.78                        Strep. pyogenes EES61                                                                        3.1    0.05   0.05   0.02   0.1    0.39                        Strep. pyogenes 930 CONST                                                                    3.1    0.05   0.05   0.05   0.1    0.78                        Strep. pyogenes 2548 INDUC                                                                   1.56   0.02   0.05   0.01   0.05   0.39                        M. luteus ATCC 9341                                                                          3.1    0.1    0.2    0.05   0.2    3.1                         M. luteus ATCC 4698                                                                          3.1    0.1    0.2    0.02   0.1    1.56                        Escherichia coli Juhl                                                                        0.1    0.005  0.05   0.02   0.02   0.05                        E. coli SS     0.02   0.002  0.002  0.0005 0.005  0.005                       E. coli DC-2   0.78   0.05   0.78   0.1    0.2    0.2                         E. coli H560   0.1    0.005  0.05   0.01   0.02   0.01                        E. coli KNK 437                                                                              0.78   0.05   0.39   0.2    0.2    0.2                         Enter. aerogenes ATCC 13048                                                                  0.2    0.02   0.05   0.05   0.1    0.05                        Klebs. pneunoniae ATCC 8045                                                                  0.05   0.01   0.005  0.005  0.01   0.01                        Providencia stuartii CMX 640                                                                 3.1    0.39   1.56   0.39   0.39   0.78                        P. aeruginosa BMH 10                                                                         0.3    0.1    0.78   0.39   0.39   0.1                         P. aeruginosa A5007                                                                          0.78   0.2    0.78   0.39   0.39   0.2                         P. aeruginosa K799/WT                                                                        0.78   0.2    0.78   0.78   0.39   0.1                         P. aeruginosa K799/61                                                                        0.1    0.02   0.05   0.02   0.05   0.02                        Pseudomonas cepacia 296I                                                                     6.2    0.78   3.1    0.78   0.78   3.1                         Acinetob. calcoaceticus CMX 669                                                              0.78   0.02   0.05   0.02   0.05   0.39                        P. aeruginosa 5263                                                                           50     3.1    12.5   3.1    6.2    12.5                        P. aeruginosa 2862                                                                           50     3.1    12.5   3.1    6.2    12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.39   0.02   0.1    0.1    0.1    1.56                        Nocardia asteroides ATCC 9970                                                                50     3.1    3.1    0.78   6.2    25                          __________________________________________________________________________    Organisms      Ex. 424                                                                              Ex. 425                                                                              Ex. 426                                                                              Ex. 427                                                                              Ex. 428                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.01   0.005  0.02   0.005  0.002  0.05                        Staph. aureus A5177                                                                          0.01   0.01   0.02   0.01   0.01   0.39                        Staph. aureus 5278                                                                           0.01   0.01   0.02   0.01   0.01   0.39                        Staph. aureus 642A                                                                           0.01   0.01   0.02   0.01   0.01   0.39                        Staph. aureus NCTC 10649M                                                                    0.01   0.005  0.02   0.01   0.002  0.39                        Staph. aureus CMX 553                                                                        0.02   0.01   0.02   0.02   0.01   0.78                        Staph. aureus 1775 Cipro. R.                                                                 0.39   0.39   1.56   0.39   0.39   >100                        Staph. epidermidis 3519                                                                      0.01   0.01   0.2    0.02   0.01   0.39                        Entero. faecium ATCC 8043                                                                    0.02   0.05   0.2    0.05   0.05   0.78                        Strep. bovis A5169                                                                           0.02   0.1    0.2    --     --     1.56                        Strep. agalactiae CMX 508                                                                    0.02   0.05   0.1    0.02   0.01   0.78                        Strep. pyogenes EES61                                                                        0.02   --     --     0.02   0.01   0.39                        Strep. pyogenes 930 CONST                                                                    0.02   --     --     0.02   0.02   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.02   0.05   0.2    0.01   0.01   0.39                        M. luteus ATCC 9341                                                                          0.05   0.1    0.2    0.05   0.05   3.1                         M. luteus ATCC 4698                                                                          0.05   0.02   0.2    0.05   0.05   1.56                        Escherichia coli Juhl                                                                        0.02   0.02   0.1    0.01   0.01   0.05                        E. coli SS     0.002  0.0005 0.005  0.0005 0.0005 0.005                       E. coli DC-2   0.1    0.2    0.78   0.1    0.1    0.2                         E. coli H560   0.02   0.05   0.1    0.01   0.01   0.01                        E. coli KNK 437                                                                              0.1    0.1    0.78   0.1    0.1    0.2                         Enter. aerogenes ATCC 13048                                                                  0.05   0.1    0.2    0.05   0.05   0.05                        Klebs. pneunoniae ATCC 8045                                                                  0.005  0.01   0.02   0.01   0.005  0.01                        Providencia stuartii CMX 640                                                                 0.78   0.39   0.78   0.78   0.39   0.78                        P. aeruginosa BMH 10                                                                         0.2    0.05   0.78   0.2    0.1    0.1                         P. aeruginosa A5007                                                                          0.39   0.39   0.78   0.39   0.39   0.2                         P. aeruginosa K799/WT                                                                        0.39   0.39   0.78   0.39   0.39   0.1                         P. aeruginosa K799/61                                                                        0.05   0.02   0.1    0.05   0.05   0.02                        Pseudomonas cepacia 296I                                                                     1.56   0.39   0.78   0.78   1.56   3.1                         Acinetob. calcoaceticus CMX 669                                                              0.02   0.02   0.2    0.01   0.02   0.39                        P. aeruginosa 5263                                                                           3.1    3.1    6.2    3.1    3.1    12.5                        P. aeruginosa 2862                                                                           3.1    3.1    25     6.2    3.1    12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.1    0.05   0.2    0.2    0.2    1.56                        Nocardia asteroides ATCC 9970                                                                3.1    3.1    6.2    0.78   1.56   25                          __________________________________________________________________________    Organisms      Ex. 429                                                                              Ex. 430                                                                              Ex. 431                                                                              Ex. 432                                                                              Ex. 433                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.01   0.05   0.1    0.1    0.01   0.05                        Staph. aureus A5177                                                                          0.01   0.1    0.1    0.1    0.02   0.39                        Staph. aureus 5278                                                                           0.05   0.05   0.1    0.1    0.02   0.39                        Staph. aureus 642A                                                                           0.2    0.05   0.1    0.1    0.02   0.39                        Staph. aureus NCTC 10649M                                                                    0.005  0.02   0.78   0.1    0.02   0.39                        Staph. aureus CMX 553                                                                        0.02   0.1    0.2    0.1    0.02   0.78                        Staph. aureus 1775 Cipro. R.                                                                 0.39   0.78   6.2    12.5   1.56   >100                        Staph. epidermidis 3519                                                                      0.05   0.1    0.1    0.1    0.02   0.39                        Entero. faecium ATCC 8043                                                                    0.1    0.39   0.78   1.56   0.2    0.78                        Strep. bovis A5169                                                                           0.2    0.39   0.78   6.2    0.78   1.56                        Strep. agalactiae CMX 508                                                                    0.1    0.2    0.78   1.56   0.1    0.78                        Strep. pyogenes EES61                                                                        0.2    0.2    0.78   1.56   0.2    0.39                        Strep. pyogenes 930 CONST                                                                    0.2    0.2    0.78   1.56   0.2    0.78                        Strep. pyogenes 2548 INDUC                                                                   0.1    0.2    0.78   1.56   0.2    0.39                        M. luteus ATCC 9341                                                                          0.2    0.39   1.56   3.1    0.2    3.1                         M. luteus ATCC 4698                                                                          0.02   0.39   0.39   1.56   0.02   1.56                        Escherichia coli Juhl                                                                        0.2    0.78   0.78   1.56   0.02   0.05                        E. coli SS     0.01   0.02   0.01   0.005  0.002  0.005                       E. coli DC-2   1.56   3.1    6.2    50     6.2    0.2                         E. coli H560   0.39   0.78   0.78   3.1    0.02   0.01                        E. coli KNK 437                                                                              1.56   3.1    6.2    25     1.56   0.2                         Enter. aerogenes ATCC 13048                                                                  0.78   1.56   3.1    6.2    1.56   0.05                        Klebs. pneunoniae ATCC 8045                                                                  0.2    0.39   0.78   12.5   3.1    0.01                        Providencia stuartii CMX 640                                                                 3.1    6.2    25     100    12.5   0.78                        P. aeruginosa BMH 10                                                                         3.1    3.1    12.5   50     3.1    0.1                         P. aeruginosa A5007                                                                          6.2    6.2    12.5   50     6.2    0.2                         P. aeruginosa K799/WT                                                                        1.56   6.2    12.5   50     12.5   0.1                         P. aeruginosa K799/61                                                                        0.2    0.39   0.78   3.1    0.39   0.02                        Pseudomonas cepacia 296I                                                                     3.1    3.1    25     100    6.2    3.1                         Acinetob. calcoaceticus CMX 669                                                              0.39   0.78   3.1    3.1    0.39   0.39                        P. aeruginosa 5263                                                                           >100   100    100    >100   100    12.5                        P. aeruginosa 2862                                                                           >100   100    100    >100   100    12.5                        Candida albicans CCH 442                                                                     >100   >100   100    >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.78   3.1    50     --     --     1.56                        Nocardia asteroides ATCC 9970                                                                6.2    6.2    50     --     --     25                          __________________________________________________________________________    Organisms      Ex. 434                                                                              Ex. 435                                                                              Ex. 436                                                                              Ex. 437                                                                              Ex. 438                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.2    0.01   0.01   0.01   0.39   0.05                        Staph. aureus A5177                                                                          0.2    0.02   0.02   0.02   0.78   0.39                        Staph. aureus 5278                                                                           0.2    0.02   0.02   0.02   0.78   0.39                        Staph. aureus 642A                                                                           0.2    0.02   0.02   0.02   0.78   0.39                        Staph. aureus NCTC 10649M                                                                    0.2    0.02   0.01   0.02   0.39   0.39                        Staph. aureus CMX 553                                                                        0.2    0.02   0.02   0.02   1.56   0.78                        Staph. aureus 1775 Cipro. R.                                                                 12.5   3.1    1.56   0.39   100    >100                        Staph. epidermidis 3519                                                                      0.2    0.02   0.02   0.02   0.39   0.39                        Entero. faecium ATCC 8043                                                                    3.1    0.1    0.1    0.02   1.56   0.78                        Strep. bovis A5169                                                                           3.1    --     --     --     0.78   1.56                        Strep. agalactiae CMX 508                                                                    1.56   0.02   0.02   0.02   0.78   0.78                        Strep. pyogenes EES61                                                                        1.56   0.1    0.02   0.02   0.78   0.39                        Strep. pyogenes 930 CONST                                                                    1.56   0.1    0.05   0.05   0.39   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.78   0.1    0.02   0.02   0.39   0.39                        M. luteus ATCC 9341                                                                          1.56   0.1    0.1    0.02   0.78   3.1                         M. luteus ATCC 4698                                                                          1.56   0.1    0.05   0.02   0.78   1.56                        Escherichia coli Juhl                                                                        0.2    0.01   0.005  0.02   0.78   0.05                        E. coli SS     0.02   0.0005 0.0005 0.0005 0.05   0.005                       E. coli DC-2   1.56   0.1    0.05   0.2    6.2    0.2                         E. coli H560   0.2    0.02   0.005  0.02   0.78   0.01                        E. coli KNK 437                                                                              0.78   0.2    0.05   0.2    6.2    0.2                         Enter. aerogenes ATCC 13048                                                                  0.39   0.05   0.02   0.05   3.1    0.05                        Klebs. pneunoniae ATCC 8045                                                                  0.1    0.005  0.005  0.005  0.39   0.01                        Providencia stuartii CMX 640                                                                 25     0.78   0.39   0.78   25     0.78                        P. aeruginosa BMH 10                                                                         1.56   0.2    0.1    0.39   0.78   0.1                         P. aeruginosa A5007                                                                          3.12   0.39   0.2    0.39   1.56   0.2                         P. aeruginosa K799/WT                                                                        6.2    0.39   0.2    0.78   3.1    0.1                         P. aeruginosa K799/61                                                                        0.78   0.05   0.02   0.05   0.39   0.02                        Pseudomonas cepacia 296I                                                                     25     0.78   0.39   0.78   100    3.1                         Acinetob. calcoaceticus CMX 669                                                              0.39   0.05   0.02   0.05   6.2    0.39                        P. aeruginosa 5263                                                                           100    6.2    3.1    6.2    25     12.5                        P. aeruginosa 2862                                                                           100    6.2    3.1    6.2    50     12.5                        Candida albicans CCH 442                                                                     >100   >100   <100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.78   0.05   0.01   0.02   0.78   1.56                        Nocardia asteroides ATCC 9970                                                                25     3.1    1.56   1.56   50     25                          __________________________________________________________________________    Organisms      Ex. 439                                                                              Ex. 440                                                                              Ex. 441                                                                              Ex. 442                                                                              Ex. 443                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.01   0.5    0.05   0.1    0.02   0.05                        Staph. aureus A5177                                                                          0.02   0.2    0.1    0.1    0.05   0.39                        Staph. aureus 5278                                                                           0.05   0.2    0.05   0.1    0.05   0.39                        Staph. aureus 642A                                                                           0.05   0.2    0.05   0.1    0.05   0.39                        Staph. aureus NCTC 10649M                                                                    0.01   0.05   0.05   0.1    0.02   0.39                        Staph. aureus CMX 553                                                                        0.1    0.39   0.1    --     0.05   0.78                        Staph. aureus 1775 Cipro. R.                                                                 6.2    12.5   6.2    3.1    1.56   >100                        Staph. epidermidis 3519                                                                      0.02   0.2    0.1    --     0.05   0.39                        Entero. faecium ATCC 8043                                                                    0.05   0.39   0.2    0.39   0.1    0.78                        Strep. bovis A5169                                                                           0.05   0.2    0.1    0.39   0.05   1.56                        Strep. agalactiae CMX 508                                                                    0.05   0.1    0.05   0.1    0.05   0.78                        Strep. pyogenes EES61                                                                        0.02   0.05   0.05   0.1    0.02   0.39                        Strep. pyogenes 930 CONST                                                                    0.02   0.2    0.1    0.1    0.02   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.02   0.1    0.1    0.1    0.02   0.39                        M. luteus ATCC 9341                                                                          0.1    0.78   0.78   1.56   0.2    3.1                         M. luteus ATCC 4698                                                                          0.1    0.39   0.2    1.56   0.1    1.56                        Escherichia coli Juhl                                                                        0.05   0.2    0.1    0.39   0.1    0.05                        E. coli SS     0.005  0.01   0.01   0.39   0.005  0.005                       E. coli DC-2   0.39   1.56   0.78   3.1    0.39   0.2                         E. coli H560   0.1    0.39   0.1    0.39   0.05   0.01                        E. coli KNK 437                                                                              0.78   1.56   0.39   3.1    0.39   0.2                         Enter. aerogenes ATCC 13048                                                                  0.1    0.78   0.39   1.56   0.39   0.05                        Klebs. pneunoniae ATCC 8045                                                                  0.1    0.1    0.05   0.2    0.05   0.01                        Providencia stuartii CMX 640                                                                 3.1    12.5   3.1    6.2    1.56   0.78                        P. aeruginosa BMH 10                                                                         0.39   3.1    0.78   3.1    0.39   0.1                         P. aeruginosa A5007                                                                          0.78   6.2    1.56   6.2    0.78   0.2                         P. aeruginosa K799/WT                                                                        0.78   6.2    3.1    12.5   0.78   0.1                         P. aeruginosa K799/61                                                                        0.1    0.39   0.2    1.56   0.1    0.02                        Pseudomonas cepacia 296I                                                                     3.1    12.5   6.2    6.2    3.1    3.1                         Acinetob. calcoaceticus CMX 669                                                              0.78   0.78   0.39   0.39   0.1    0.39                        P. aeruginosa 5263                                                                           12.5   100    25     <100   12.5   12.5                        P. aeruginosa 2862                                                                           12.5   100    25     <100   12.5   12.5                        Candida albicans CCH 442                                                                     <100   <100   <100   <100   <100   >100                        Myco. smegmatis ATCC 114                                                                     0.1    0.39   0.2    0.39   0.05   1.56                        Nocardia asteroides ATCC 9970                                                                6.2    6.2    25     12.5   1.56   25                          __________________________________________________________________________    Organisms      Ex. 444                                                                              Ex. 445                                                                              Ex. 446                                                                              Ex. 447                                                                              Ex. 448                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.02   0.05   0.39   0.1    0.01   0.05                        Staph. aureus A5177                                                                          0.05   0.1    0.78   0.2    0.02   0.39                        Staph. aureus 5278                                                                           0.02   0.1    0.78   0.2    0.02   0.39                        Staph. aureus 642A                                                                           0.05   0.05   0.78   0.1    0.02   0.39                        Staph. aureus NCTC 10649M                                                                    0.02   0.05   0.39   0.02   0.02   0.39                        Staph. aureus CMX 553                                                                        0.05   0.1    0.78   0.05   0.02   0.78                        Staph. aureus 1775 Cipro. R.                                                                 0.39   6.2    50     0.78   0.78   >100                        Staph. epidermidis 3519                                                                      0.05   0.1    0.78   0.05   0.02   0.39                        Entero. faecium ATCC 8043                                                                    0.05   0.1    3.1    0.39   0.1    0.78                        Strep. bovis A5169                                                                           0.05   0.1    1.56   0.39   0.2    1.56                        Strep. agalactiae CMX 508                                                                    0.05   0.1    0.78   0.39   0.05   0.78                        Strep. pyogenes EES61                                                                        0.05   0.1    0.78   0.2    0.05   0.39                        Strep. pyogenes 930 CONST                                                                    0.05   0.1    1.56   0.39   0.1    0.78                        Strep. pyogenes 2548 INDUC                                                                   0.05   0.05   1.56   0.2    0.1    0.39                        M. luteus ATCC 9341                                                                          0.2    0.2    12.5   0.39   0.2    3.1                         M. luteus ATCC 4698                                                                          0.05   0.2    3.1    0.2    0.1    1.56                        Escherichia coli Juhl                                                                        0.02   0.02   6.2    0.39   0.05   0.05                        E. coli SS     0.002  0.005  0.2    0.05   0.0005 0.005                       E. coli DC-2   0.39   0.2    100    3.1    0.39   0.2                         E. coli H560   0.02   0.05   12.5   0.39   0.05   0.01                        E. coli KNK 437                                                                              0.2    0.2    50     1.56   0.39   0.2                         Enter. aerogenes ATCC 13048                                                                  0.05   0.05   12.5   0.78   0.2    0.05                        Klebs. pneunoniae ATCC 8045                                                                  0.01   0.02   1.56   0.39   0.02   0.01                        Providencia stuartii CMX 640                                                                 0.78   0.78   100    3.1    1.56   0.78                        P. aeruginosa BMH 10                                                                         0.39   0.1    100    3.1    0.39   0.1                         P. aeruginosa A5007                                                                          0.39   0.2    100    3.1    0.78   0.2                         P. aeruginosa K799/WT                                                                        0.39   0.2    50     3.1    0.78   0.1                         P. aeruginosa K799/61                                                                        0.1    0.05   1.56   0.39   0.1    0.02                        Pseudomonas cepacia 296I                                                                     1.56   3.1    6.2    3.1    1.56   3.1                         Acinetob. calcoaceticus CMX 669                                                              0.05   0.2    3.1    0.39   0.1    0.39                        P. aeruginosa 5263                                                                           6.2    6.2    >100   >100   12.5   12.5                        P. aeruginosa 2862                                                                           6.2    6.2    >100   >100   12.5   12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   100    >100                        Myco. smegmatis ATCC 114                                                                     0.2    0.39   6.2    6.2    0.39   1.56                        Nocardia asteroides ATCC 9970                                                                3.1    25     >100   25     12.5   25                          __________________________________________________________________________    Organisms      Ex. 449                                                                              Ex. 450                                                                              Ex. 451                                                                              Ex. 452                                                                              Ex. 453                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.002  0.005  0.02   0.05   0.02   0.05                        Staph. aureus A5177                                                                          0.005  0.01   0.02   0.05   0.02   0.39                        Staph. aureus 5278                                                                           0.005  0.01   0.02   0.1    0.02   0.39                        Staph. aureus 642A                                                                           0.005  0.01   0.02   0.05   0.05   0.39                        Staph. aureus NCTC 10649M                                                                    0.002  0.01   0.02   0.05   0.02   0.39                        Staph. aureus CMX 553                                                                        0.005  0.02   0.02   0.05   0.02   0.78                        Staph. aureus 1775 Cipro. R.                                                                 0.1    0.39   0.39   1.56   0.78   >100                        Staph. epidermidis 3519                                                                      0.005  0.02   0.02   0.1    0.1    0.39                        Entero. faecium ATCC 8043                                                                    0.02   0.1    0.1    0.2    0.1    0.78                        Strep. bovis A5169                                                                           0.01   --     0.2    0.2    0.2    1.56                        Strep. agalactiae CMX 508                                                                    0.002  0.1    0.1    0.1    0.05   0.78                        Strep. pyogenes EES61                                                                        0.002  0.1    0.1    0.1    --     0.39                        Strep. pyogenes 930 CONST                                                                    0.002  0.1    0.05   0.2    --     0.78                        Strep. pyogenes 2548 INDUC                                                                   0.002  0.02   0.05   0.2    0.1    0.39                        M. luteus ATCC 9341                                                                          0.05   0.1    0.1    0.2    0.2    3.1                         M. luteus ATCC 4698                                                                          0.02   0.05   0.1    0.2    0.2    1.56                        Escherichia coli Juhl                                                                        0.02   0.02   0.1    0.1    0.5    0.05                        E. coli SS     0.0005 0.0005 0.002  0.001  0.02   0.005                       E. coli DC-2   0.2    0.39   0.78   0.78   0.39   0.2                         E. coli H560   0.01   0.02   0.05   0.1    0.1    0.01                        E. coli KNK 437                                                                              0.2    0.2    1.56   0.78   0.39   0.2                         Enter. aerogenes ATCC 13048                                                                  0.1    0.1    0.1    0.2    0.2    0.05                        Klebs. pneunoniae ATCC 8045                                                                  0.01   0.02   0.02   1.56   0.05   0.01                        Providencia stuartii CMX 640                                                                 0.78   1.56   1.56   3.1    1.56   0.78                        P. aeruginosa BMH 10                                                                         0.39   0.39   0.78   0.78   0.39   0.1                         P. aeruginosa A5007                                                                          0.78   0.78   1.56   1.56   0.78   0.2                         P. aeruginosa K799/WT                                                                        0.78   0.78   3.1    3.1    1.56   0.1                         P. aeruginosa K799/61                                                                        0.05   0.05   0.1    0.2    0.2    0.02                        Pseudomonas cepacia 296I                                                                     3.1    3.1    1.56   1.56   3.1    3.1                         Acinetob. calcoaceticus CMX 669                                                              0.02   0.05   0.1    0.1    0.1    0.39                        P. aeruginosa 5263                                                                           12.5   12.5   25     25     12.5   12.5                        P. aeruginosa 2862                                                                           12.5   12.5   50     25     25     12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.02   0.1    0.1    0.05   25     1.56                        Nocardia asteroides ATCC 9970                                                                0.78   1.56   0.78   0.39   6.2    25                          __________________________________________________________________________    Organisms      Ex. 454                                                                              Ex. 455                                                                              Ex. 456                                                                              Ex. 457                                                                              Ex. 458                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.05   1.56   0.02   0.02   0.02   0.05                        Staph. aureus A5177                                                                          0.05   1.56   0.02   0.05   0.02   0.39                        Staph. aureus 5278                                                                           0.05   1.56   0.02   0.05   0.02   0.39                        Staph. aureus 642A                                                                           0.05   1.56   0.02   0.02   0.02   0.39                        Staph. aureus NCTC 10649M                                                                    0.05   1.56   0.02   0.05   0.02   0.39                        Staph. aureus CMX 553                                                                        0.1    --     0.02   0.1    0.02   0.78                        Staph. aureus 1775 Cipro. R.                                                                 1.56   >100   0.39   6.2    0.39   >100                        Staph. epidermidis 3519                                                                      0.1    --     0.02   0.05   0.02   0.39                        Entero. faecium ATCC 8043                                                                    0.39   50     0.2    0.2    0.2    0.78                        Strep. bovis A5169                                                                           0.78   >100   0.2    0.1    0.2    1.56                        Strep. agalactiae CMX 508                                                                    0.39   12.5   0.1    0.05   0.1    0.78                        Strep. pyogenes EES61                                                                        --     25     0.1    0.05   0.05   0.39                        Strep. pyogenes 930 CONST                                                                    --     12.5   0.1    0.05   0.05   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.39   12.5   0.1    0.05   0.05   0.39                        M. luteus ATCC 9341                                                                          0.39   >100   0.1    0.2    0.1    3.1                         M. luteus ATCC 4698                                                                          0.39   >100   0.1    0.2    0.1    1.56                        Escherichia coli Juhl                                                                        0.39   3.1    0.1    0.05   0.01   0.05                        E. coli SS     0.02   3.1    0.01   0.001  0.0005 0.005                       E. coli DC-2   0.78   >100   0.78   0.2    0.2    0.2                         E. coli H560   0.39   6.2    0.1    0.05   0.02   0.01                        E. coli KNK 437                                                                              12.5   100    0.39   0.2    0.2    0.2                         Enter. aerogenes ATCC 13048                                                                  1.56   6.2    0.39   0.1    0.1    0.05                        Klebs. pneunoniae ATCC 8045                                                                  0.1    1.56   0.1    0.39   0.39   0.01                        Providencia stuartii CMX 640                                                                 6.2    >100   3.1    1.56   1.56   0.78                        P. aeruginosa BMH 10                                                                         3.1    >100   1.56   0.2    0.2    0.1                         P. aeruginosa A5007                                                                          100    >100   1.56   0.39   0.39   0.2                         P. aeruginosa K799/WT                                                                        100    >100   6.2    1.56   1.56   0.1                         P. aeruginosa K799/61                                                                        0.2    6.2    0.39   0.2    0.1    0.02                        Pseudomonas cepacia 296I                                                                     0.78   12.5   6.2    0.39   0.39   3.1                         Acinetob. calcoaceticus CMX 669                                                              0.2    6.2    0.1    0.1    0.05   0.39                        P. aeruginosa 5263                                                                           >100   >100   25     6.2    12.5   12.5                        P. aeruginosa 2862                                                                           >100   >100   25     6.2    6.2    12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   50     25     >100                        Myco. smegmatis ATCC 114                                                                     0.78   12.5   0.2    --     --     1.56                        Nocardia asteroides ATCC 9970                                                                >100   50     1.56   --     --     25                          __________________________________________________________________________    Organisms      Ex. 459                                                                              Ex. 460                                                                              Ex. 461                                                                              Ex. 462                                                                              Ex. 463                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.02   0.05   0.05   0.001  0.005  0.05                        Staph. aureus A5177                                                                          0.05   0.05   0.1    0.005  0.01   0.39                        Staph. aureus 5278                                                                           0.05   0.05   0.1    0.005  0.01   0.39                        Staph. aureus 642A                                                                           0.05   0.05   0.1    0.005  0.01   0.39                        Staph. aureus NCTC 10649M                                                                    0.05   0.05   0.1    0.002  0.005  0.39                        Staph. aureus CMX 553                                                                        0.05   0.05   0.1    0.005  0.01   0.78                        Staph. aureus 1775 Cipro. R.                                                                 0.78   3.1    6.2    0.2    0.39   >100                        Staph. epidermidis 3519                                                                      0.05   0.1    0.1    0.005  0.01   0.39                        Entero. faecium ATCC 8043                                                                    0.1    0.1    0.2    0.05   0.05   0.78                        Strep. bovis A5169                                                                           0.1    0.1    0.39   0.05   0.05   1.56                        Strep. agalactiae CMX 508                                                                    0.02   0.05   0.39   0.02   0.05   0.78                        Strep. pyogenes EES61                                                                        --     --     --     0.02   0.05   0.39                        Strep. pyogenes 930 CONST                                                                    --     --     --     0.02   0.05   0.78                        Strep. pyogenes 2548 INDUC                                                                   0.05   0.02   0.1    0.02   0.05   0.39                        M. luteus ATCC 9341                                                                          0.1    0.2    0.2    0.05   0.05   3.1                         M. luteus ATCC 4698                                                                          0.1    0.2    0.2    0.02   0.02   1.56                        Escherichia coli Juhl                                                                        0.01   0.02   0.05   0.05   0.05   0.05                        E. coli SS     0.002  0.001  0.02   0.0005 0.002  0.005                       E. coli DC-2   0.2    0.1    0.39   0.39   0.39   0.2                         E. coli H560   0.05   0.005  0.05   0.05   0.05   0.01                        E. coli KNK 437                                                                              0.2    0.1    0.39   0.39   0.2    0.2                         Enter. aerogenes ATCC 13048                                                                  0.1    0.05   0.05   0.1    0.1    0.05                        Klebs. pneunoniae ATCC 8045                                                                  0.01   0.01   0.02   0.02   0.02   0.01                        Providencia stuartii CMX 640                                                                 0.78   0.39   0.39   0.39   0.78   0.78                        P. aeruginosa BMH 10                                                                         0.39   0.1    0.39   0.39   0.39   0.1                         P. aeruginosa A5007                                                                          0.78   0.2    0.39   0.39   0.39   0.2                         P. aeruginosa K799/WT                                                                        0.78   0.39   0.39   0.39   0.39   0.1                         P. aeruginosa K799/61                                                                        0.1    0.02   0.05   0.02   0.02   0.02                        Pseudomonas cepacia 296I                                                                     3.1    0.78   0.78   0.39   0.39   3.1                         Acinetob. calcoaceticus CMX 669                                                              0.05   0.05   0.1    0.05   0.1    0.39                        P. aeruginosa 5263                                                                           6.2    3.1    6.2    3.1    6.2    12.5                        P. aeruginosa 2862                                                                           6.2    3.1    6.2    6.2    6.2    12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   >100   >100                        Myco. smegmatis ATCC 114                                                                     0.1    0.05   0.1    0.1    0.39   1.56                        Nocardia asteroides ATCC 9970                                                                3.1    1.56   3.1    3.1    3.1    25                          __________________________________________________________________________    Organisms      Ex. 464                                                                              Ex. 465                                                                              Ex. 466                                                                              Ex. 467                                                                              Ex. 469                                                                              Cntl                        __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                     0.005  0.1    0.05   0.39   0.002  0.05                        Staph. aureus A5177                                                                          0.005  0.2    0.05   0.39   0.005  0.39                        Staph. aureus 5278                                                                           0.005  0.2    0.05   0.39   0.002  0.39                        Staph. aureus 642A                                                                           0.005  0.2    0.1    0.39   0.005  0.39                        Staph. aureus NCTC 10649M                                                                    0.005  0.2    0.05   0.39   0.002  0.39                        Staph. aureus CMX 553                                                                        0.005  0.2    0.1    0.39   0.005  0.78                        Staph. aureus 1775 Cipro. R.                                                                 0.39   100    1.56   25     0.02   >100                        Staph. epidermidis 3519                                                                      0.005  0.2    0.05   0.39   0.005  0.39                        Entero. faecium ATCC 8043                                                                    0.05   1.56   0.2    0.78   0.01   0.78                        Strep. bovis A5169                                                                           0.1    25     --     --     0.002  1.56                        Strep. agalactiae CMX 508                                                                    0.1    1.56   0.1    0.78   0.002  0.78                        Strep. pyogenes EES61                                                                        0.1    6.2    0.2    0.78   0.002  0.39                        Strep. pyogenes 930 CONST                                                                    0.1    6.2    0.1    1.56   0.002  0.78                        Strep. pyogenes 2548 INDUC                                                                   0.05   1.56   0.1    0.78   0.002  0.39                        M. luteus ATCC 9341                                                                          0.1    12.5   0.2    1.56   0.005  3.1                         M. luteus ATCC 4698                                                                          0.05   1.56   0.2    1.56   0.005  1.56                        Escherichia coli Juhl                                                                        0.1    1.56   0.02   0.39   0.01   0.05                        E. coli SS     0.0005 0.05   0.002  0.05   0.001  0.005                       E. coli DC-2   0.78   100    0.2    1.56   0.05   0.2                         E. coli H560   0.1    3.1    0.02   0.39   0.01   0.01                        E. coli KNK 437                                                                              0.39   50     0.2    1.56   0.1    0.2                         Enter. aerogenes ATCC 13048                                                                  0.1    6.2    0.1    0.78   0.05   0.05                        Klebs. pneunoniae ATCC 8045                                                                  0.05   0.78   0.02   0.2    0.005  0.01                        Providencia stuartii CMX 640                                                                 1.56   100    1.56   6.2    0.1    0.78                        P. aeruginosa BMH 10                                                                         0.78   100    0.2    1.56   0.1    0.1                         P. aeruginosa A5007                                                                          0.78   100    0.39   3.1    0.1    0.2                         P. aeruginosa K799/WT                                                                        0.78   50     0.78   6.2    0.1    0.1                         P. aeruginosa K799/61                                                                        0.05   1.56   0.1    0.39   0.05   0.02                        Pseudomonas cepacia 296I                                                                     0.78   12.5   1.56   12.5   0.78   3.1                         Acinetob. calcoaceticus CMX 669                                                              0.1    6.2    0.1    0.78   0.01   0.39                        P. aeruginosa 5263                                                                           50     >100   6.2    50     1.56   12.5                        P. aeruginosa 2862                                                                           50     >100   6.2    50     1.56   12.5                        Candida albicans CCH 442                                                                     >100   >100   >100   >100   25     >100                        Myco. smegmatis ATCC 114                                                                     0.1    12.5   0.1    3.1    0.01   1.56                        Nocardia asteroides ATCC 9970                                                                6.2    50     1.56   25     0.2    25                          __________________________________________________________________________    Organisms        Ex. 469 Ex. 470                                                                              Ex. 471  Ex. 472                                                                              Cntl                          __________________________________________________________________________    Staph. aureus ATCC 6538P                                                                       0.05    0.05   0.005    0.1    0.05                          Staph. aureus A5177                                                                            0.05    0.05   0.005    0.1    0.39                          Staph. aureus 5278                                                                             0.05    0.05   0.005    0.1    0.39                          Staph. aureus 642A                                                                             0.05    0.05   0.01     0.1    0.39                          Staph. aureus NCTC 10649M                                                                      0.05    0.05   0.005    0.1    0.39                          Staph. aureus CMX 553                                                                          0.1     0.1    0.05     0.2    0.78                          Staph. aureus 1775 Cipro. R.                                                                   3.1     0.78   0.39     12.5   >100                          Staph. epidermidis 3519                                                                        0.05    0.05   0.02     0.1    0.39                          Entero. faecium ATCC 8043                                                                      0.1     0.2    0.02     0.2    0.78                          Strep. bovis A5169                                                                             0.1     0.02   0.02     --     1.56                          Strep. agalactiae CMX 508                                                                      0.1     0.02   0.0005   0.2    0.78                          Strep. pyogenes EES61                                                                          0.1     0.02   0.0005   0.1    0.39                          Strep. pyogenes 930 CONST                                                                      0.1     0.05   0.02     0.1    0.78                          Strep. pyogenes 2548 INDUC                                                                     0.05    0.05   0.005    0.1    0.39                          M. luteus ATCC 9341                                                                            0.2     0.39   0.1      0.78   3.1                           M. luteus ATCC 4698                                                                            0.2     0.2    0.05     0.78   1.56                          Escherichia coli Juhl                                                                          0.01    0.39   0.005    0.05   0.05                          E. coli SS       0.005   0.02   0.0005   0.01   0.005                         E. coli DC-2     0.1     1.56   0.2      0.78   0.2                           E. coli H560     0.02    0.2    0.02     0.1    0.01                          E. coli KNK 437  0.1     1.56   0.1      0.78   0.2                           Enter. aerogenes ATCC 13048                                                                    0.05    0.78   0.05     0.2    0.05                          Klebs. pneunoniae ATCC 8045                                                                    0.005   0.1    0.005    0.05   0.01                          Providencia stuartii CMX 640                                                                   0.39    3.1    0.78     1.56   0.78                          P. aeruginosa BMH 10                                                                           0.1     1.56   0.2      0.39   0.1                           P. aeruginosa A5007                                                                            0.2     3.1    0.39     0.78   0.2                           P. aeruginosa K799/WT                                                                          0.2     3.1    0.39     0.78   0.1                           P. aeruginosa K799/61                                                                          0.05    0.39   0.05     0.05   0.02                          Pseudomonas cepacia 296I                                                                       1.56    12.5   3.1      3.1    3.1                           Acinetob. calcoaceticus CMX 669                                                                0.1     0.39   0.05     0.78   0.39                          P. aeruginosa 5263                                                                             3.1     50     6.2      25     12.5                          P. aeruginosa 2862                                                                             3.1     50     6.2      25     12.5                          Candida albicans CCH 442                                                                       >100    >100   >100     >100   >100                          Myco. smegmatis ATCC 114                                                                       0.2     1.56   0.05     0.1    1.56                          Nocardia asteroides ATCC 9970                                                                  1.56    1.56   3.1      12.5   25                            __________________________________________________________________________

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

What is claimed is:
 1. A compound having the formula ##STR348## or apharmaceutically acceptable salt, ester or amide thereof, wherein R¹ informula (I) is selected from (a) loweralkyl, (b) loweralkenyl, (c)halo(loweralkyl), (d) loweralkoxy, (e) cycloalkyl of from three to eightcarbon atoms, (f) phenyl, (g) substituted phenyl, (h) halo, (i) cyano,(j) nitro, (k) bicycloalkyl, (1) loweralkynyl, (m) loweralkoxycarbonyl,(n) nitrogen-containing aromatic heterocycle, selected from the groupconsisting of pyridine, pyrazine, pyrimidine, pyrrazole, imidazole,thiazole, oxazole, isoxazole, thiadiazole and oxadiazole, (o)halo-substituted nitrogen-containing aromatic heterocycle, where thenitrogen-containing aromatic heterocycle is as defined above, (p) a 4-,5- or 6-membered cyclic ether, and (q) --NR⁷ R⁸ where R⁷ and R⁸ areindependently selected from the group consisting of_hydrogen, loweralkyland alkanoyl of from one to eight carbon atoms or, taken together withthe nitrogen atom to which they are attached, R⁷ and R⁸ form a 5-, 6- or7-membered heterocycle;R² in formula (I) is selected from (a) halogen,(b) loweralkyl, (c) loweralkenyl, (d) cycloalkyl of from three to eightcarbons, (e) cycloalkenyl of from four to eight carbons, (f)loweralkoxy, (g) aryloxy, (h) aryl(loweralkyl)oxy, (i) aryl(loweralkyl),(j) cycloalkyl(loweralkyl), (k) amino, (1) (loweralkyl)amino, (m)aryl(loweralkyl)amino, (n) hydroxy-substituted (loweralkyl)amino, (o)phenyl, (p) substituted phenyl, (q) bicyclic nitrogen-containingheterocycle, (r) nitrogen-containing aromatic heterocycle as definedabove, (s) nitrogen-containing heterocycle having the formula ##STR349##(t) non-nitrogen-containing heterocycle having the formula ##STR350##where x is zero, one, two or three; R⁹ is selected from the groupconsisting of (i) --(CH₂)_(m) - where m is one, two or three, and (ii)--(CH₂)_(n) R¹³ (CH₂)_(p) - where R¹³ is selected from --S--, --O-- and--NH--, R¹⁰ is CH₂, or when R⁹ is selected from option (i) may be O, Sor N, n is one or two, and p is one or two; and R³¹ is --(CH₂)_(q) R³² -where R³² is selected from --S-- and --O--, and q is one, two or three;and Y is independently selected at each occurrence from the groupconsisting, of:(i) loweralkyl, (ii) hydroxy, (iii) halogen, (iv)halo(loweralkyl), (v) hydroxy-substituted loweralkyl, (vi)loweralkenylamino, (vii) loweralkylamino, (viii) loweralkoxy, (ix)(loweralkoxy)loweralkylamino, (x) loweralkoxy(loweralkyl), (xi)loweralkoxy(loweralkoxy)(loweralkyl), (xii) hydroxy-substitutedloweralkyl, (xiii) imino, (xiv) alkoxycarbonyl, (xv) carbamoyl, (xvi)aryl(loweralkyl), (xvii) aminoxy (xviii) amino(loweralkyl), (xix)halo(loweralkyl)amino, (xx) halo(loweralkyl)amino(loweralkyl), (xxi)thioloweralkoxy(loweralkyl), (xxii) aminothioloweralkoxy, (xxiii)cycloalkyl of from three to six carbon atoms, (xxiv)cycloalkyl(loweralkyl), (xxv) cycloalkylamino, (xxvi) phenyl, (xxvii)substituted phenyl, (xxviii) substituted phenyl(loweralkyl) (xxix)nitrogen-containing aromatic heterocycle as defined above, (xxx) --NR¹¹R¹² where R¹¹ and R¹² are independently selected from hydrogen andloweralkyl or, when one of R¹¹ and R¹² is hydrogen, the other isalkanoyl of from one to eight carbon atoms, an alpha-amino acid, or apolypeptide residue of from two to five amino acids, and (xxxi)--C(R²¹)(R²²)NH₂ where R²¹ and R²² are independently selected from amonghydrogen, loweralkyl, hydroxy-substituted loweralkyl, amino(loweralkyl),loweralkoxy-(loweralkyl), thioloweralkoxy(loweralkyl), cycloalkyl offrom three to six carbon atoms, and loweralkyl substituted withnitrogen-containing aromatic heterocycle as defined above or, takentogether with the carbon atom to which they are attached, R²¹ and R²²form a ring structure selected from cycloalkyl of from three to sixcarbon atoms and nitrogen-containing heterocycle; R³ is selected fromthe group consisting of hydrogen, halogen and loweralkoxy; R⁴ isselected from the group consisting of hydrogen, loweralkyl, apharmaceutically acceptable cation, and a prodrug ester group; R⁵ isselected from the group consisting of (a) hydrogen, (b) halogen, (c)hydroxy, (d) loweralkyl, (e) halo(loweralkyl), (f) loweralkoxy, and (g)--NR¹³ R¹⁴ where R¹³ and R¹⁴ are independently selected from the groupconsisting of hydrogen, loweralkyl, hydroxy-substituted loweralkyl,loweralkoxy(loweralkyl), and alkanoyl of from one to eight carbon atoms;and A is ═CR⁶ -, where R⁶ is selected from the group consisting of (a)hydrogen, (b) halogen, (c) loweralkyl, (d) halo(loweralkyl), (e)hydroxy-substituted loweralkyl, (f) loweralkoxy(loweralkyl), (h)loweralkoxy, and (i) amino(loweralkyl); provided that, when R⁵ ishydrogen and A is ═CH--, R¹ is not unsubstituted phenyl.
 2. A compoundaccording to claim 1 wherein R⁶ is selected from the group consisting ofhalogen, loweralkyl, halo(loweralkyl), hydroxy-substituted loweralkyl,loweralkoxy(loweralkyl), loweralkoxy, and amino(loweralkyl).
 3. Acompound according to claim 1 wherein R² is selected from the groupconsisting of bicyclic nitrogen-containing heterocycle and anitrogen-containing heterocycle having the formula ##STR351## where R⁹,Y and x are as previously defined.
 4. A compound according to claim 3wherein R² is selected from the group consisting of ##STR352## where Yand x are as previously defined.
 5. A compound according to claim 4wherein x is one or two and Y is selected from the group consisting of--NR¹¹ R¹² and --C(R²¹)(R²²)NH₂, where R¹¹, R¹², R²¹ and R²² are aspreviously defined.
 6. A compound according to claim 2 wherein R⁶ ismethyl.
 7. A compound according to claim 2 wherein R³ is halogen.
 8. Acompound according to claim 7 wherein R⁵ is selected from the groupconsisting of hydrogen, loweralkyl, halo(loweralkyl), and --NR¹³ R¹⁴where R¹³ and R¹⁴ are as previously defined.
 9. A compound according toclaim 8 wherein R¹ is selected from the group consisting of cycloalkylof from three to eight carbon atoms and substituted phenyl.
 10. Acompound according to claim 9 wherein R⁶ is selected from the groupconsisting of halogen, loweralkyl, and loweralkoxy.
 11. A compoundaccording to claim 10 wherein R³ is halogen.
 12. A compound according toclaim 11 wherein R⁵ is selected from the group consisting of hydrogen,loweralkyl, halo(loweralkyl), and --NR¹³ R¹⁴ where R¹³ and R¹⁴ are aspreviously defined.
 13. A compound according to claim 12 wherein R¹ isselected from the group consisting of cycloalkyl of from three to eightcarbon atoms and substituted phenyl.
 14. A compound according to claim13 wherein R² is selected from the group consisting of bicyclicnitrogen-containing heterocycle and a nitrogen-containing heterocyclehaving the formula ##STR353## where R⁹, Y and x are as previouslydefined.
 15. A compound according to claim 14 wherein R² is selectedfrom the group consisting of ##STR354## where Y and x are as previouslydefined.
 16. A compound according to claim 15 wherein x is one or twoand Y is selected from the group consisting of --NR¹¹ R¹² and--C(R²¹)(R²²)NH₂, where R¹¹, R¹², R²¹ and R²² are as previously defined.17. A compound according to claim 1 having the formula ##STR355## or apharmaceutically acceptable salt, ester or amide thereof, wherein R² isselected from the group consisting of bicyclic nitrogen-containingheterocycle and a nitrogen-containing heterocycle having the formula##STR356## and where R⁴, R⁹, Y and x are as previously defined.
 18. Acompound according to claim 17 wherein R² is selected from the groupconsisting of ##STR357## where Y and x are as previously defined.
 19. Acompound according to claim 18 wherein x is one or two and Y is selectedfrom the group consisting of --NR¹¹ R¹² and --C(R²¹)(R²²)NH₂, where R¹¹,R¹², R²¹ and R²² are as previously defined.
 20. A compound according toclaim 1 selected from the group consistingof:8-(3-aminopyrrolidin-1-yl)-1-ethyl-4H-quinolizine-4-one-3-carboxylicacid;8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(aminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(2S,4S-4-amino-2-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-aminoazetidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3(S)-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-methyl-1-piperazinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-piperazinyl-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-8-(2-((N-methyl)aminemethyl)-4-morpholinyl)-4-oxo-4H-quinolizine-3-carboxylic acid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(1,2,3,4-tetrahydro-2-isoquinolinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(5-amino-1,2,3,4-tetrahydro-2-isoquinolinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(1-pyrrolyl)-1-piperidinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(cis-3,5-dimethyl-1-piperazinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(2,7-diaza-7-bicyclo[3,3,0]octyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(2,8-diaza-8-bicyclo[4,3,0]nonyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-(1-pyrrolyl)-1-pyrrolidinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-8-(3-hydroxy-1-pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-9-chloro-7-fluoro-8-(3-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid trifluoroacetic acid;8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylicacid.1cyclopropyl-8-(2,7-diaza-7-bicyclo[3,3,0]oct-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(2,8-diaza-8-bicyclo[4,3,0]nonyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-(1-pyrrolyl)-1-pyrrolidinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-8-(3-hydroxy-1-pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-9-chloro-7-fluoro-8-(3-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-1-pyrrolidinyl)-4-oxo-4H-quinolizine3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-1-pyrrolidinyl)-4-oxo-4H-quinolizine3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-8-(3(R)-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3-carboxylicacid;(3S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2,3,4ij]quinolizine-5-carboxylicacid; (R)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2,3,4-ij]quinolizine-5-carboxylicacid;9-fluoro-10-(1-morpholinyl)-2H,3H,6H-6-oxo-pyrano[2,3,4-ij]quinolizine-5-carboxylicacid;(3S)-10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2,3,4-ij]quinolizine-5-carboxylicacid;3(S)-10-(3-aminomethyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2,3,4-ij]quinolizine-5-carboxylicacid;3(S)-10-((2S,4S)-4-amino-2-methyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano-[2,3,4-ij]quinolizine-5-carboxylicacid;3(S)-9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-2H,3H,6H-6-oxo-pyrano[2,3,4-ij]quinolizine-5-carboxylicacid; 9-fluoro-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2,3,4-ij]quinolizine-3-carboxylic acid;8-(2,4-dimethyl-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(methylamino)-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(methylamino)-1-morpholinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(S)-(methylamino)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(S)-(1-(methylamino)methyl)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4-H-quinolizine-3-carboxylicacid;8-(3-(S)-(1-(ethylamino)methyl)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(octahydropyrrolo[3,4-c]pyrrol-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(octahydropyrrolo[3,4-c]pyridin-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(cis-4-amino-3-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(trans-4-amino-3-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-methyl-4-spirocyclopropylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; 8-(2S ,4S-4-amino-2-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-(fluoro)methyl-4-oxo-4H-quinolizine-3-carboxylic acid;8-(3-dimethylaminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3carboxylicacid;(3R)-8-(3-dimethylaminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; (3R,1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;(3S,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; (3R,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1cyclopropyl-8-((R,S)-3-fluoropyrrolidine)7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(4-(1-piperidyl)-1-piperidyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(4-(1-piperidyl)-1-piperidyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(4-(2-pyridyl)-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-((2-amino)thioethoxy)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; (3R,1S)-8-(3-(1-amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; (3R,1S)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4oxo-4H-quinolizine-3-carboxylicacid;(3R,1S)-8-(3-(1-amino-3-methylpropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4H-quinolizine-3-carboxylicacid;8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; (3R,1S)-8-(3-(1-amino-2-hydroxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(1-aminobutyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3-aminopyrrolidinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3-aminomethylpyrrolidinyl)-4H-quinolizine-3-carboxylic acid;3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-norvalylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylicacid; 3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylicacid;3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanyl-(S)-alanylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-6-methyl-4-oxo-8-(3-aminopyrrolidinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-4H-8-(1-imidazolyl)-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-amino-1-pyrrolidinyl)-1-ethyl-7-fluoro-4H-4-oxo-9-methyl-quinolizine-3-carboxylicacid;8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-9-ethyl-7-fluoro-4H-4-oxo-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(1,2,3-triazol-1-yl)-1-pyrrolidinyl)-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(cis-3-amino-4-methyl-1-pyrrolidinyl)-quinolizine-3-carboxylicacid;8-(2-aminoethyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(ethylaminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-4H-9-methyl-8-(2-methyl-2-8-diaza-8-bicyclo[4,3,0]nonyl)-4-oxo-quinolizine-3-carboxylicacid; 1-cycloptopyl-7-fluoro-4H-8-((1S,4S)-2,5-diaza-bicyclo[2,2,1]heptan-2-yl)-9-methyl-4-oxo-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(2-pyridinyl)-1-pyrrolidinyl)-quinolizine-3-carboxylicacid;8-((1R*,2S*,6R*)-2-amino-8-azabicyclo[4,3,0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid; 8-((1R *,2R *, 6R*)-2-amino-8-azabicyclo[4,3,0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid; 8-((1a,5a,6a)-6-amino-3-azabicyclo[3,1,0]hexan-3-yl))-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(trans-3-amino-4-fluoro-1-pyrrolidinyl))-1-cyclopropyl-9-methyl-7-fluoro-4H-4-oxo-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-4H-8-(1-homopiperazinyl))-9-methyl-4-oxo-quinolizine-3-carboxylicacid;7,9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo-1-phenyl-quinolizine-3-carboxylicacid;8-(spiro-1,3-dioxacyclopentane[2,3]-1-piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-amino-4-methoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(4-amino-4-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(4-(2-hydroxyethyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(4-(methoxymethyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-amino-3-methylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-pyrrolylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-amino-3-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-amino-4-(1',3'-dioxolanyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-amino-4-hydroxy-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(4-(1-(N-ethylamino)methyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-8-(3-hydroxy-4-methylaminopyrrolidinyl)-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-aminomethylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;8-(2-aminomethyl-4-morpholinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(1-(methylamino)methypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(methyl(methylenedioxy)methyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(S)-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(S)-(N-ethyl-N-methylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(4-(2'-(N-methylamino)methyl-1',3'-dioxolanyl)piperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3,3,0]octan-1-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(3-fluoromethylpiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine;1-cyclopropyl-8-(4-(N,N-dimethyl)aminopiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1cyclopropyl-8-(6-amino-3-azabicyclo[3,3,0]octyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-8-((2-aza-4-(dimethylaminomethyl)bicyclo[4,3,0]non-2-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizinecarboxylic acid;1-cyclopropyl-8-(3-aza-6-(L-alanylamino)-6-methylbicyclo[3,3,0]octane)-7-fluoro-9-methyl-4-oxo-4H-quinolizinecarboxylic acid;(3R,1R)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; (3R,1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(S)-(acetylamino)pyrrolidinyl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-carbamoylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-hydroxypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-hydroxymethylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(R)-hydroxypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid; (3R)-9-fluoro-3-methyl-10-(piperazin-1-yl)-2H, 3H, 6H-6-oxo-pyrano[2,3,4-ij]acid;1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4,3,0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4,3,0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3,1,0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-aminomethyl-3-fluoro-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(S)-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(R)-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(1-amino-5-aza-spiro[2,4]heptan-5-yl-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid Diastereomer A;8-(1-amino-5-aza-spiro[2,4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid Diastereomer B;8-(3-(1-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(S*)-(1-(S)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(R)-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(S)-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(octahydropyrrolo[3,2-b]pyridin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(8-amino-6-azaspiro[3,4]oct-6-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(2-aminomethyl-4-hydroxypyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(R)-(aminomethyl)morpholin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(R)-(L-alanylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(5-aminooctahydroindol-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3carboxylicacid;8-(3-(2-piperidyl)piperidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(5-amino-decahydroisoquinolin-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(2,7-diazabicyclo[3,3,0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine--3-carboxylicacid;8-(3,7-diazabicyclo[3,3,0]oct-3-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-carboxypyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(2,2,2-trifluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-((2-fluoroethyl)aminomethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;-(3a-amino-octahydroisoindol-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(6-amino-2-aza-spiro[3,3]non-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid (Isomer (I));8-(3-amino-3-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(S)-hydroxymethylazetidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-aminomethyI-3-trifluoromethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(octahydropyrrolo[3,4-c]pyrid-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(cyclopropylamino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(6-amino-2-aza-spiro[3,3]non-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid (Isomer (II));8-(2,7-diazabicyclo[3,3,0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid Isomer A;8-(2,7-diazabicyclo[3,3,0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid Isomer B;8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(S)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(2-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(2-(S)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(2-(S)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(R)-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(S)-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(1-amino-1-cyclopropyl-methyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(R)-(pyrrolidin-2-(S)-yl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(aminomethyl)azetidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; and8-(3-(7-amino-5-azaspiro[2,4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;and the pharmaceutically acceptable salts, esters and amidesthereof.
 21. A compound according to claim 20 selected from the groupconsistingof:8-(3-(aminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3(S)-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; 8(3R,1S)-8-(3-(1-amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(1-aminobutyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; (3R,1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino-1-piperdinyl)-4H-quinolizine-3-carboxylicacid;1-(3-(S)-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3,3,0]octan-1-yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(6-amino-3-azabicyclo[3,3,0]octyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; 8-((1R*,2S*,6R*)-2-amino-8-azabicyclo[4,3,0]nonan-8-yl))-1-cycloptopyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylicacid; 8-((1R *,2R*,6R*)-2-amino-8-azabicyclo[4,3,0]nonan-8-yl))-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; (3R,1S)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4oxo-4H-quinolizine-3-carboxylicacid;8-(3-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;(3S,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; (3R,1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; (3 R,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cycloptopyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4,3,0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4,3,0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3,1,0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; and8-(3-(7-amino-5-azaspiro[2,4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;and the pharmaceutically acceptable salts, esters and amidesthereof.
 22. A compound according to claim 20 selected from the groupconsistingof:8-(3(S)-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-amino-1-pyrrolidinyl-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; (3R,1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; (3R,1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(S,S,2,8-diaza-8-bicyclo[4,3,0]nonyl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid; 1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4,3,0]nonyl)-7-fluoro-4H-9-methyl-4oxo-quinolizine-3-carboxylicacid;1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3,1,0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid;8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylicacid; and(8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid; and 8-(3-(7-amino-5-azaspiro[2,4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid;and the pharmaceutically acceptable salts, esters and amidesthereof.
 23. A pharmaceutical composition comprising a compoundaccording to claim 1 in combination with a pharmaceutically acceptablecarrier.
 24. A pharmaceutical composition comprising a compoundaccording to claim 6 in combination with a pharmaceutically acceptablecarrier.
 25. A pharmaceutical composition comprising a compoundaccording to claim 20 in combination with a pharmaceutically acceptablecarrier.
 26. A pharmaceutical composition comprising a compoundaccording to claim 23 in combination with a pharmaceutically acceptablecarrier.
 27. A method of treating a bacterial infection in a human orveterinary patient, comprising administering to the patient atherapeutically effective amount of a compound according to claim
 1. 28.A method of treating a bacterial infection in a human or veterinarypatient, comprising administering to the patient a therapeuticallyeffective amount of a compound according to claim
 6. 29. A method oftreating a bacterial infection in a human or veterinary patient,comprising administering to the patient a therapeutically effectiveamount of a compound according to claim
 20. 30. A method of treating abacterial infection in a human or veterinary patient, comprisingadministering to the patient a therapeutically effective amount of acompound according to claim
 23. 31. A synthetic intermediate selectedfrom the group consistingof:4-t-butoxy-3-chloro-2,5,6-trifluoropyridine;4-t-butoxy-2,3,6-trifluoropyridine;4-t-butoxy-2,3,6-trifluoro-5-methylpyridine;4-t-butoxy-2,5-difluoro-3-methylpyridine; 2-(4-t-butoxy-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile;2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile;2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetic acid; ethyl2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetate;2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetaldehyde;2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneethanol;2-(2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylethylidinyl)-1,3-propanedicarboxylicacid, diethyl ester; and8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4h-quinolizine-3-carboxylicacid ethyl ester.